Compounds useful as kinase inhibitors

ABSTRACT

This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton&#39;s tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton&#39;s tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.

This application is a continuation of U.S. application Ser. No.17/122,103 filed on Dec. 15, 2020, which is a continuation of U.S.application Ser. No. 15/930,657 filed on May 13, 2020, which is acontinuation of U.S. application Ser. No. 16/063,542 filed on Jun. 18,2018, which is a National Stage application under 35 U.S.C. § 371 ofInternational Application No. PCT/GB2016/053968, filed Dec. 16, 2016,which claims the benefit of priority to GB 1613945.3, filed Aug. 15,2016 and GB 1522245.8, filed Dec. 16, 2015.

This invention relates to compounds. More specifically, the inventionrelates to compounds useful as kinase inhibitors, along with processesto prepare the compounds and uses of the compounds. Specifically, theinvention relates to inhibitors of Bruton's tyrosine kinase (BTK).

BACKGROUND

Kinases are a class of enzyme that control the transfer of phosphategroups from phosphate donor groups, for example ATP, to specificsubstrates. Protein kinases are a large subset of kinases that play acentral role in the regulation of a wide variety of cellular signallingand processes and BTK is one such protein kinase.

BTK is a member of the src-related Tec family of cytoplasmic tyrosinekinases. BTK plays a key role in the B-cell receptor (BCR) signallingpathway of B-cells, which is required for the development, activationand survival of B-cells. BTK inhibitors have therefore been developedwith the aim of treating B-cell malignancies that are dependent on BCRsignalling, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin'slymphoma (NHL) (Buggy 2012). BTK is also expressed in specific myeloidcells including, monocytes/macrophages, neutrophils and mast cells. Inthese myeloid cells, BTK has been indicated in the immune complexmediated activation of FcγR and FcεR, which is believed to contribute tothe pathogenesis of rheumatoid arthritis (RA) (Whang 2014). In addition,BTK is required for the maturation of osteoclast cells and so inhibitingBTK could prevent the bone erosion that is associated with RA. Thecritical role of BTK in both B-cells and myeloid cells has led to BTKbecoming an attractive target for the treatment of not only B-cellmalignancies but also for the treatment of autoimmune diseases.

Ibrutinib is an irreversible BTK inhibitor that has been approved forthe treatment of CLL, mantle cell lymphoma (MCL) and Waldenstrom'smacroglobulinemia (WM). Since Ibrutinib was first disclosed there havebeen a number of patent applications concerned with structures closelyrelated to Ibrutinib, for example see WO 2012/158843, WO 2012/158764, WO2011/153514, WO 2011/046964, US 2010/0254905, US 2010/0144705, U.S. Pat.No. 7,718,662, WO, 2008/054827 and WO 2008/121742.

Further Btk inhibitors are disclosed in WO 2013/010136, U.S. Pat. No.9,090,621, WO 2015/127310, WO 2015/095099 and US 2014/221333. Kinaseinhibitors are also disclosed in U.S. Pat. No. 6,660,744, US2002/0156081, US 2003/0225098 and WO 01/19829.

Ibrutinib also irreversibly binds to interleukin-2 inducible tyrosinekinase (ITK) (Dubovsky 2013). ITK plays a critical role inFcR-stimulated natural killer (NK) cell function that is required forantibody dependent NK cell mediated cytotoxicity (ADCC). ADCC is themechanism that anti-CD20 antibodies, such as rituximab are believed toactivate and ibrutinib has been shown to antagonise this mechanism invitro (Kohrt 2014). As rituximab-combination chemotherapy is today'sstandard of care in B-cell malignancies, it would be desirable to have aBTK inhibitor with high selectivity for BTK over ITK.

In the clinic, adverse events have included atrial fibrillation,diarrhea, rash, arthralgia and bleeding (IMBRUVICA package insert 2014).Known BTK inhibitors, e.g. ibrutinib are also known to havegastrointestinal side effects, which are considered to be as a result ofa secondary EGFR inhibitory activity. It is therefore desirable to havea BTK inhibitor with high BTK inhibition and low EGFR inhibition toreduce or avoid the gastrointestinal side effects.

Irreversible and covalent reversible BTK inhibitors specifically targeta cysteine residue C481 within BTK. Following treatment with ibrutinib,cases of primary and secondary resistance have emerged. Mutations withinBTK such as C481S, C481Y, C481R, C481F have been reported in theliterature and clearly interfere with drug binding (Woyach 2014;Maddocks 2015). It has been predicted that the incidence of observedresistance will increase as clinical use outside clinical trials expandsover time (Zhang 2015).

Therefore, an aim of the present invention is to provide BTK inhibitorswith a different binding mode more specifically reversible inhibitors.In addition, the invention aims to provide BTK inhibitors with highselectivity for BTK inhibition over EGFR and ITK inhibition.

Furthermore, it is an aim of certain embodiments of this invention toprovide new cancer treatments. In particular, it is an aim of certainembodiments of this invention to provide compounds which have comparableactivity to existing cancer treatments but are also effective againstmutations. One of the aspects of the invention focus on providing BTKinhibitors effective against the C481 mutations.

It is an aim of certain embodiments of this invention to providecompounds which exhibit reduced cytotoxicity relative to prior artcompounds and existing therapies.

Another aim of certain embodiments of this invention is to providecompounds having a convenient pharmacokinetic profile and a suitableduration of action following dosing. A further aim of certainembodiments of this invention is to provide compounds in which themetabolised fragment or fragments of the drug after absorption are GRAS(Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of theabove aims.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with the present invention there is provided compounds asdisclosed below. Furthermore, the invention provides compounds capableof inhibiting Bruton's tyrosine kinase (BTK) and the use of thesecompounds in inhibiting BTK. In accordance with the invention there isprovided a method of treating conditions modulated by BTK. The inventionprovides compounds for use in treating a condition which is modulated byBTK.

In a first aspect of the invention there is provided a compoundaccording to formula (I) or pharmaceutically acceptable salts thereof:

whereinA represents a ring selected from unsubstituted or substituted: phenyl,pyridine, pyridazine, pyrimidine, or pyrazine, wherein when substitutedA is substituted with from 1 to 4 R⁷;R¹ represents a group selected from: C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈alkoxy, C₂₋₈ alkyl ether, —C(O)R^(A), C₃₋₁₀ carbocyclic group, 3 to 10membered heterocyclic group, C₁₋₈ alkyl substituted with C₃₋₁₀carbocyclic group, and C₁₋₈ alkyl substituted with 3 to 10 memberedheterocyclic group, wherein each of the aforementioned groups areunsubstituted or substituted with 1 to 5 substituents independentlyselected from: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₂₋₄ alkylether, —OR^(A), —NR^(A)R^(B), —CN, ═O, —OC(O)R^(A), —C(O)R^(A),—C(O)OR^(A), —NR^(A)C(O)R^(B), —C(O)NR^(A)R^(B), —NR^(A)S(O)₂R^(B),—S(O)₂NR^(A)R^(B), benzoyl, a 5 or 6 membered heterocycloaryl, a 3 to 6membered heterocycloalkyl ring, C₁₋₄ alkyl substituted with —OR^(A) andC₁₋₄ alkoxy substituted with —OR^(A), or a single atom of R¹ issubstituted twice so as to form a 3 to 6 membered heterocycloalkyl orcycloalkyl ring;R² represents a group selected from: —OH, halo, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 3 to 10 memberedheterocyclic group, alkyl substituted with —OR^(C), C₁₋₈ alkylsubstituted with C₃₋₁₀ carbocyclic group, alkyl substituted with 3 to 10membered heterocyclic group, and —NR^(C)R^(D);R³ represents —C(O)NR^(E)R^(F), C₁₋₆ alkyl substituted with —OR^(G), orC₁₋₆ haloalkyl;R^(4a) and R^(4b) are independently at each occurrence selected from: H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, and C₁₋₆ alkylsubstituted with —OR^(H);R⁵ is H or C₁₋₄ alkyl;R⁶ is a group selected from a substituted or unsubstituted: phenyl or a5 or 6 membered heteroaryl ring, wherein, when substituted, R⁶ containsfrom 1 to 5 substituents independently selected at each occurrence from:halo, —OR^(I), —NR^(I)R^(J), —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₁₋₆alkyl substituted with —OR^(I);R⁷ is selected from: H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,and C₁₋₆ alkyl substituted with —OR^(H);m is 1 or 2;R^(A) and R^(B) are, at each occurrence, independently selected from: H,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, phenyl, benzyl, or C₁₋₄ alkylsubstituted with —OR^(H);R^(C), R^(D), R^(E) and R^(F) are, at each occurrence, independentlyselected from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, unsubstituted C₃₋₁₀carbocyclic group, C₁₋₄ alkyl substituted with unsubstituted C₃₋₁₀carbocyclic group, C₁₋₄ alkyl substituted with C₃₋₁₀ carbocyclic groupsubstituted with 1 or 2 R^(H) or —OR^(H), and 3 to 10 memberedheterocyclic group;R^(G), R^(I), and R^(J) are independently at each occurrence selectedfrom: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄ alkylsubstituted with —OR^(H); andR^(H) is selected from H or C₁₋₄ alkyl.

In an embodiment A is unsubstituted phenyl, unsubstituted pyridine,phenyl substituted by from 1 to 4 R⁷, or pyridine substituted by from 1to 4 R⁷.

Preferably, A is unsubstituted phenyl, unsubstituted pyridine,unsubstituted pyridazine, unsubstituted pyrimidine, unsubstitutedpyrazine, or phenyl substituted with 1 or 2 R⁷.

In an embodiment, A is unsubstituted phenyl, unsubstituted pyrdinyl orphenyl substituted with from 1 to 4 R⁷ (optionally 1 or 2 R⁷). In anembodiment, A is unsubstituted phenyl or phenyl substituted with from 1to 4 R⁷.

As the skilled person will note from the structural formula of formula(I), group “A” is substituted by two groups, shown below (it may also beoptionally substituted by from 1 to 4 R⁷).

These two groups may be para substituted on A. In other words, the twogroups may be 1,4-substituted on A.

In an embodiment, A may be:

wherein 0, 1 or 2 of A¹, A², A⁴ and A⁵ are independently selected from Nand the remainder are CR⁷.

Accordingly, the compounds according to formula (I) may be compounds offormula (II) or pharmaceutically acceptable salts thereof:

wherein 0, 1 or 2 of A¹, A², A⁴ and A⁵ are independently selected from Nand the remainder are CR⁷.

In embodiments 0 or 1 of A¹, A², A⁴ and A⁵ are N, of the remaining A¹,A², A⁴ and A⁵ 0 or 1 are CR⁷ and the remainder are CH.

In embodiments A¹, A⁴ and A⁵ are CH and A² is CR⁷ and R⁷ is selectedfrom fluoro, methyl, methoxy, or —CH₂OH. In embodiments A², A⁴ and A⁵are CH and A¹ is CR⁷ and R⁷ is selected from H, fluoro, methyl, methoxy,or —CH₂OH. In embodiments A¹, A⁴ and A⁵ are CH and A² is N. Inembodiments A², A⁴ and A⁵ are CH and A¹ is N. In embodiments A¹ and A⁵are CH and A² and A⁴ are N. In embodiments A¹ and A⁵ are N and A² and A⁴are CH. In embodiments A¹ and A⁴ are CH and A² and A⁵ are N. Inembodiments A¹ and A² are CH and A⁴ and A⁵ are N.

In embodiments A¹ and A⁵ are CH and A² and A⁴ are CR⁷ and R⁷ is selectedfrom fluoro, methyl, methoxy, or —CH₂OH. In embodiments A¹ and A² are CHand A⁴ and A⁵ are CR⁷ and R⁷ is selected from fluoro, methyl, methoxy,or —CH₂OH. In embodiments A² and A⁴ are CH and A¹ and A⁵ are CR⁷ and R⁷is selected from fluoro, methyl, methoxy, or —CH₂OH. In embodiments A¹and A⁴ are CH and A² and A⁵ are CR⁷ and R⁷ is selected from fluoro,methyl, methoxy, or —CH₂OH.

Optionally, R⁷ may be selected from: H, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,and C₁₋₆ alkyl substituted with —OR^(H). Preferably, R⁷ may be selectedfrom: H, fluoro, methyl, methoxy, and —CH₂OH. Preferably, R⁷ is H.

In embodiments A may be selected from:

In embodiments A may be selected from:

In embodiments A may be selected from:

In preferred embodiments, A is selected from:

In embodiments R⁶ is a group selected from a substituted orunsubstituted: phenyl or 6 membered heteroaryl ring. Preferably, R⁶ is agroup selected from a substituted: phenyl or 6 membered heteroaryl ring,substituted with 1 or 2 (preferably 1) methoxy (—OMe) group.

In embodiments R⁶ is a group selected from a substituted orunsubstituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, orthiodiazolyl.

Preferably, R⁶ is a group selected from a substituted: phenyl, pyridyl,pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,triazolyl, oxadiazolyl, or thiodiazolyl, wherein R⁶ contains from 1, 2or 3 substituents independently selected at each occurrence from: halo,—OR^(I), —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₁₋₆ alkyl substitutedwith —OR^(I), optionally R^(I) is selected from: H, methyl, ethyl, —CF₃,—CH₂—OR^(H) and —CH₂CH₂—OR^(H). Preferably, R^(I) is H or methyl.

As the skilled person will be aware, based on the depiction of thestructural formula of compounds of the invention, R⁶ is attached to theremainder of the compound of the invention via a carbonyl (—C(═O)—)group. When R⁶ is substituted by 1, 2 or 3 substituents R⁶ issubstituted by the carbonyl group (connecting R⁶ to the remainder of thecompound) and a further 1, 2 or 3 substituents. In preferred embodimentsone of the substituents is substituted adjacent to the —C(═O)—. In otherwords, one of the substituents is substituted ortho to the carbonylgroup (—C(═O)—). Preferably, the substituent of the 1, 2 or 3substituents that is substituted on R⁶ ortho to the carbonyl group ismethoxy.

In embodiments R⁶ is substituted or unsubstituted: phenyl or pyridyl(preferably substituted. In particularly preferred embodiments R⁶ issubstituted phenyl.

Preferably, R⁶ contains from 1, 2 or 3 substituents independentlyselected at each occurrence from: fluoro, chloro, methoxy, ethoxy,isopropoxy, —CN, methyl, ethyl, trifluoromethyl, trifluoroethyl or—OCF₃. In embodiments, R⁶ contains 1 or 2 substituents independentlyselected at each occurrence from: fluoro, methoxy or methyl. Preferably,R⁶ contains 1 methoxy substituent or 2 substituents that are fluoro andmethoxy.

A particularly preferred substituent for R⁶ is methoxy. Accordingly, inpreferred embodiments R⁶ is a group selected from a methoxy substituted:phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiodiazolyl.Optionally, R⁶ is a group selected from a methoxy substituted: phenyl,pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl.

Particularly preferred substituents for R⁶ are methoxy and fluoro.Accordingly, in preferred embodiments R⁶ is a group selected from afluoro and methoxy substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl,or thiodiazolyl. Optionally, R⁶ is a group selected from a fluoro andmethoxy substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl orpyrimidinyl.

R⁶ may be methoxyphenyl or fluoromethoxyphenyl. R⁶ may be methoxyphenyl.As the skilled person will be aware R⁶ is attached to the remainder ofthe compound of the invention via a carbonyl (—C(═O)—) group. When R⁶ ismethoxy phenyl the phenyl group of R⁶ is substituted by the carbonylgroup (connecting the phenyl ring to the remainder of the compound) anda methoxy group. In preferred embodiments where R⁶ is methoxy phenyl,the methoxy group is substituted adjacent to the —C(═O)—. In otherwords, the methoxy group is substituted ortho to the carbonyl group(—C(═O)—) Accordingly, in an embodiment compounds according to formula(I) are compounds of formulae (IIIa) and (IIIb):

Hence, in preferred embodiments R⁶ is 2-methoxyphen-1-yl.

R⁶ may be fluoromethoxyphenyl. As the skilled person will be aware R⁶ isattached to the remainder of the compound of the invention via acarbonyl (—C(═O)—) group. When R⁶ is fluoromethoxyphenyl the phenylgroup of R⁶ is substituted by the carbonyl group (connecting the phenylring to the remainder of the compound), a fluoro group and a methoxygroup. In preferred embodiments where R⁶ is fluoromethoxyphenyl, themethoxy group is substituted adjacent to the —C(═O)— and the fluorogroup is substituted opposite the methoxy group. In other words, themethoy group is substituted ortho to the carbonyl group (—C(═O)—) andthe fluoro group is attached para to the methoxy group. Accordingly, inan embodiment compounds according to formula (I) are compounds offormulae (IIIc) and (IIId):

Hence, in preferred embodiments R⁶ is 5-fluoro-2-methoxyphen-1-yl.

In embodiments R⁶ is 2-methoxyphen-1-yl or 5-fluoro-2-methoxyphen-1-yl.

R⁵ may be H or methyl. Preferably, R⁵ is H.

R^(4a) and R^(4b) may be independently selected at each occurrence from:H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₁₋₆ alkyl substituted with —OR^(H).Optionally, R^(4a) and R^(4b) may be independently selected at eachoccurrence from: H, methyl, ethyl, cyclopropyl, or —CH₂OH. Optionally,R^(4a) is H and R^(4b) may be selected from: H, methyl, ethyl,cyclopropyl, or —CH₂OH. Optionally, R^(4a) is H and R^(4b) is selectedfrom: H, methyl or —CH₂OH. Preferably, R^(4a) is H and R^(4b) is H.

In embodiments m is 1.

In embodiments m is 1 and R^(4a) and R^(4b) are H. In embodiments, m is1, R^(4a) and R^(4b) are H, and R⁵ is H. In embodiments, m is 1, R^(4a)and R^(4b) are H, R⁵ is H, and R⁶ is fluoromethoxyphenyl ormethoxyphenyl. In embodiments m is 1, R^(4a) and R^(4b) are H, and A isunsubstituted phenyl or phenyl substituted by one R⁷. In embodiments, mis 1, R^(4a) and R^(4b) are H, R⁵ is H, and A is unsubstituted phenyl orphenyl substituted by one R⁷. In embodiments, m is 1, R^(4a) and R^(4b)are H, R⁵ is H, R⁶ is fluoromethoxyphenyl or methoxyphenyl, and A isunsubstituted phenyl or phenyl substituted by one R⁷. R⁷ may be selectedfrom: fluoro, methyl, methoxy, and —CH₂OH.

In embodiments m is 1 and R^(4a) and R^(4b) are H. In embodiments, m is1, R^(4a) and R^(4b) are H, and R⁵ is H. In embodiments, m is 1, R^(4a)and R^(4b) are H, R⁵ is H, and R⁶ is methoxyphenyl. In embodiments m is1, R^(4a) and R^(4b) are H, and A is unsubstituted phenyl or phenylsubstituted by one R⁷. In embodiments, m is 1, R^(4a) and R^(4b) are H,R⁵ is H, and A is unsubstituted phenyl or phenyl substituted by one R⁷.In embodiments, m is 1, R^(4a) and R^(4b) are H, R⁵ is H, R⁶ ismethoxyphenyl, and A is unsubstituted phenyl or phenyl substituted byone R⁷. R⁷ may be selected from: fluoro, methyl, methoxy, and —CH₂OH.

In embodiments R³ represents —C(O)NR^(E)R^(F). Preferably, R³ represents—C(O)NHMe or —C(O)NH₂.

In embodiments the compound according to formula (I) may be compounds offormula (IV) or pharmaceutically acceptable salts thereof:

In embodiments R² represents a group selected from: halo, C₁₋₈ alkyl,C₁₋₈ haloalkyl, and —NR^(C)R^(D). Preferably, R² represents Cl, CHF₂,CF₃, NH₂, NHPh, NHMe, NHEt, and NH^(i-)Pr.

In embodiments the compound according to formula (I) may be compounds offormulae (IVa), (IVb), (IVc) or (IVd) or pharmaceutically acceptablesalts thereof:

Additionally or alternatively in embodiments the compound according toformula (I) may be compounds of formulae (IVe) or (IVf) orpharmaceutically acceptable salts thereof:

In an embodiment R^(C) and R^(D) are, at each occurrence, independentlyselected from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, unsubstituted C₃₋₁₀carbocyclic group (optionally C₃₋₆ carbocyclic group or phenyl), 3 to 10membered heterocyclic group (optionally 3 to 6 membered heterocyclicgroup). Preferably, R^(C) and R^(D) are independently selected from: H,methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl,phenyl, pyridyl, and sec-butyl. For example, R^(C) is H and R^(D) isselected from: H, methyl, ethyl, isopropyl, difluoromethyl,trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl.

In an embodiment R^(C) and R^(D) are, at each occurrence, independentlyselected from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, unsubstituted C₃₋₁₀carbocyclic group (optionally C₃₋₆ carbocyclic group), 3 to 10 memberedheterocyclic group (optionally 3 to 6 membered heterocyclic group).Preferably, R^(C) and R^(D) are independently selected from: H, methyl,ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, andsec-butyl. Particularly preferred embodiments R^(C) and R^(D) are H.

In embodiments R^(E) and R^(F) are, at each occurrence, independentlyselected from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, unsubstituted C₃₋₁₀carbocyclic group (optionally C₃₋₆ carbocyclic group), 3 to 10 memberedheterocyclic group (optionally 3 to 6 membered heterocyclic group). Inembodiments R^(E) and R^(F) are, at each occurrence, independentlyselected from: H, C₁₋₄ alkyl, (preferably R^(E) and R^(F) are, at eachoccurrence, independently selected from: H, methyl, and ethyl). Inembodiments R^(E) and R^(F) are H.

In embodiments R^(C), R^(D), R^(E) and R^(F) are H.

In embodiments the compound according to formula (I) may be compounds offormulae (Va) and (Vb) or pharmaceutically acceptable salts thereof:

R² represents a group selected from: —OH, halo, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 3 to 10 memberedheterocyclic group, C₁₋₈ alkyl substituted with —OR^(C), C₁₋₈ alkylsubstituted with C₃₋₁₀ carbocyclic group, C₁₋₈ alkyl substituted with 3to 10 membered heterocyclic group, and —NR^(C)R^(D).

In embodiments R² represents a group selected from: halo, C₁₋₈ alkyl or—NR^(C)R^(D), wherein R^(C) and R^(D) are, at each occurrence,independently selected from: H or C₁₋₄ alkyl.

In embodiments R² represents a group selected from: fluoro, methyl,ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, morpholinyl,—CH₂OH, and —NR^(C)R^(D), wherein R^(C) and R^(D) are, at eachoccurrence, independently selected from: H, methyl, ethyl, isopropyl,trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl.

Preferably, R² is NH₂ or Me.

In embodiments R³ represents —C(O)NR^(E)R^(F), C₁₋₆ alkyl substitutedwith —OR^(G), or C₁₋₆ haloalkyl, optionally wherein R^(E) and R^(F) are,at each occurrence, independently selected from: H or C₁₋₄ alkyl(preferably R^(E) and R^(F) are, at each occurrence, independentlyselected from: H, methyl, and ethyl, and R^(G) is selected from: H orC₁₋₄ alkyl).

In embodiments one of R^(E) and R^(F) are H and the other is selectedfrom

In embodiments R³ represents —C(O)NH₂, —C(O)NHMe, —CH₂OH, CH(OH)CH₃,—CF₃, or —CHF₂.

Preferably, R³ represents —C(O)NH₂.

In embodiments R² is NH₂ or Me and R³ is —C(O)NH₂. In a particularlypreferred embodiment R² is NH₂ and R³ is —C(O)NH₂.

In embodiments m is 1, R^(4a) and R^(4b) are H, and R² is NH₂ and R³ is—C(O)NH₂. In embodiments, m is 1, R^(4a) and R^(4b) are H, R⁵ is H, andR² is NH₂ and R³ is —C(O)NH₂. In embodiments, m is 1, R^(4a) and R^(4b)are H, R⁵ is H, R⁶ is fluoromethoxyphenyl or methoxyphenyl, R² is NH₂,and R³ is —C(O)NH₂. In embodiments, m is 1, R^(4a) and R^(4b) are H, R⁵is H, R⁶ is methoxyphenyl, R² is NH₂, and R³ is —C(O)NH₂.

R¹ represents a group selected from: C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈alkyl ether, —C(O)R^(A), C₃₋₁₀ carbocyclic group, 3 to 10 memberedheterocyclic group, C₁₋₈ alkyl substituted with C₃₋₁₀ carbocyclic group,and C₁₋₈ alkyl substituted with 3 to 10 membered heterocyclic group,wherein each of the aforementioned groups are unsubstituted orsubstituted with 1 to 5 substituents selected from: halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₂₋₄ alkyl ether, —OR^(A), —CN, ═O,—C(O)OR^(A), —C(O)NR^(A)R^(B), a 3 to 6 membered heterocycloalkyl ring,C₁₋₄ alkyl substituted with —OR^(A), C₁₋₄ alkoxy substituted with—OR^(A); wherein R^(A) and R^(B) are independently selected from: H,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, benzyl or C₁₋₄ alkylsubstituted with —OR^(H).

R¹ represents a group selected from: C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈alkyl ether, —C(O)R^(A), C₃₋₁₀ carbocyclic group, 3 to 10 memberedheterocyclic group, C₁₋₈ alkyl substituted with C₃₋₁₀ carbocyclic group,and C₁₋₈ alkyl substituted with 3 to 10 membered heterocyclic group,wherein each of the aforementioned groups are unsubstituted orsubstituted with 1 to 5 substituents selected from: halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₂₋₄ alkyl ether, —OR^(A), —CN, ═O,—C(O)OR^(A), C₁₋₄ alkyl substituted with —OR^(A), C₁₋₄ alkoxysubstituted with —OR^(A); wherein R^(A) is selected from: H, C₁₋₄ alkyl,C₁₋₄ haloalkyl, benzyl or C₁₋₄ alkyl substituted with —OR^(H).

R¹ represents a group selected from: C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkyl ether, —C(O)R^(A), C₃₋₁₀ cycloalkyl (preferably C₃₋₆ cycloalkyl),C₆₋₁₀ aryl (preferably phenyl or indanyl), 3 to 10 memberedheterocycloalkyl (optionally 3 to 6 membered), 3 to 10 memberedheteroaryl (optionally 3 to 6 membered, for example 5 or 6 membered),C₁₋₆ alkyl substituted with C₃₋₁₀ cycloalkyl (preferably C₃₋₆cycloalkyl), C₁₋₆ alkyl substituted with C₆₋₁₀ aryl (preferably phenyl),C₁₋₆ alkyl substituted with 3 to 10 membered heterocycloalkyl(optionally 3 to 6 membered), and C₁₋₆ alkyl substituted with 3 to 10membered heteroaryl (optionally 3 to 6 membered, for example 5 or 6membered), wherein each of the aforementioned groups are unsubstitutedor substituted with 1 to 5 substituents selected from: halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₂₋₄ alkyl ether, —OR^(A), —CN, ═O,—C(O)OR^(A), —C(O)NR^(A)R^(B), a 3 to 6 membered heterocycloalkyl ring,C₁₋₄ alkyl substituted with —OR^(A), C₁₋₄ alkoxy substituted with—OR^(A), wherein R^(A) is selected from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,benzyl or C₁₋₄ alkyl substituted with —OR^(H).

In embodiments R¹ is selected from substituted or unsubstituted: methyl,ethyl, iso-propyl, propyl, hexyl, tert-hexyl, tert-butyl,trifluoroethyl, trifluoropropyl, trifluorobutyl, difluoropropyl,chloropropyl, propyl ether, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, indanyl, bicyclo[3.1.0]hexyl, oxetane,tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, phenyl,pyridyl, thiazolyl, C₁₋₈ alkyl (preferably methyl or ethyl) substitutedwith oxetane, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withmorpholine, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withtetrazole, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withpiperidine, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withcyclohexyl, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withcyclopentyl, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withtetrahydropyranyl, C₁₋₈ alkyl (preferably methyl or ethyl) substitutedwith pyrolidinyl, C₁₋₈ alkyl (preferably methyl or ethyl) substitutedwith pyridinyl, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withphenyl, C₁₋₈ alkyl (preferably methyl or ethyl) substituted withtetrohydrofuran, and C₁₋₈ alkyl (preferably methyl or ethyl) substitutedwith cyclopropyl.

In embodiments R¹ is selected from substituted or unsubstituted: methyl,ethyl, iso-propyl, tert-hexyl, tert-butyl, trifluoro, ethyl, propylether, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl,bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C₁₋₈alkyl (preferably methyl or ethyl) substituted with oxetane, C₁₋₈ alkyl(preferably methyl or ethyl) substituted with morpholine, C₁₋₈ alkyl(preferably methyl or ethyl) substituted with tetrazole, C₁₋₈ alkyl(preferably methyl or ethyl) substituted with piperidine, and C₁₋₈ alkyl(preferably methyl or ethyl) substituted with cyclohexyl.

Preferably R¹ is substituted with 1 to 5 substituents (optionally 1 to4) selected from: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₂₋₄alkyl ether, —OR^(A), —CN, ═O, —C(O)OR^(A), —C(O)NR^(A)R^(B), 5 or 6membered heteroaryl, a 3 to 6 membered heterocycloalkyl ring, C₁₋₄ alkylsubstituted with —OR^(A), C₁₋₄ alkoxy substituted with —OR^(A) or asingle atom of R¹ is substituted twice so as to form a 3 to 6 memberedheterocycloalkyl or cycloalkyl ring.

In embodiments R¹ is substituted with 1 to 4 substituents selected from:—OH, ═O, —OMe, —CN, methyl, ethyl, propyl, isopropyl, tert-butyl, CF₃,Cl, F, —OBn, —CO₂H, —CO₂Me, —CO₂Et, —C(O)NH₂, —C(O)NHMe, —C(O)NMe₂,—C(O)NH₀Me, pyridinyl, pyrolidinyl, oxetanyl, tetrahydropyranyl, ortetrahydrofuranyl or a single atom of R¹ is substituted twice so as toform a oxirane or oxetane.

Optionally R¹ is substituted with 1 to 5 substituents (optionally 1 to3) selected from: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₂₋₄alkyl ether, —OR^(A), —CN, ═O, —C(O)OR^(A), C₁₋₄ alkyl substituted with—OR^(A), C₁₋₄ alkoxy substituted with —OR^(A). In embodiments R¹ issubstituted with 1 to 3 substituents selected from: —OH, ═O, —OMe, —CN,methyl, CF₃, Cl, F, —OBn, or —CO₂Et.

In embodiments R¹ is selected from substituted or unsubstituted: methyl,ethyl, iso-propyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl,bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C₁₋₈alkyl (preferably methyl or ethyl) substituted with oxetane, C₁₋₈ alkyl(preferably methyl or ethyl) substituted with morpholine, C₁₋₈ alkyl(preferably methyl or ethyl) substituted with tetrazole, C₁₋₈ alkyl(preferably methyl or ethyl) substituted with piperidine, and C₁₋₈ alkyl(preferably methyl or ethyl) substituted with cyclohexyl,

-   -   wherein R¹ is substituted with 1 to 5 substituents selected        from: —OH, ═O, —OMe, —CN, methyl, CF₃, Cl, F, —OBn, or —CO₂Et.

In embodiments R¹ is selected from substituted or unsubstituted: methyl,ethyl, iso-propyl, tert-hexyl, tert-butyl, trifluoroethyl,

-   -   wherein R¹ is substituted with 1 to 5 substituents selected        from: —OH, ═O, —OMe, —CN, methyl, CF₃, Cl, F, —OBn, or —CO₂Et.

R¹ may be selected from:

R¹ may be selected from:

In embodiments R¹ is selected from substituted or unsubstituted: C₃₋₁₀carbocyclic group, wherein when substituted R¹ is substituted with 1 to5 substituents selected from: halo, C₁₋₄ alkyl, or —OR^(A), whereinR^(A) is selected from H or C₁₋₄ alkyl.

In embodiments R¹ is selected from substituted or unsubstituted: C₃₋₆cycloalkyl or phenyl, wherein when substituted R¹ is substituted with 1to 5 substituents selected from: halo, C₁₋₄ alkyl, or —OR^(A), whereinR^(A) is selected from H or C₁₋₄ alkyl.

In preferred embodiments R¹ is selected from substituted orunsubstituted: cyclohexyl, phenyl, cyclobutyl, cyclopentyl,bicyclo[3.1.0]hexyl, piperidinyl, pyrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl,(cyclopropyl)ethyl, or (tetrahydropyranyl)ethyl. Accordingly, R¹ may beselected from:

In preferred embodiments R¹ is selected from substituted orunsubstituted: cyclohexyl, phenyl, cyclobutyl, cyclopentyl orbicyclo[3.1.0]hexyl. Preferably, R¹ may be selected from:

In preferred embodiments R¹ is selected from substituted orunsubstituted: piperidinyl, pyrolidinyl, tetrahydropyranyl,tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl,(cyclopropyl)ethyl, or (tetrahydropyranyl)ethyl. Accordingly, R¹ may beselected from:

In an embodiment the compound according to formula (I) may be compoundsof formulae (VIa) and (VIb) or pharmaceutically acceptable saltsthereof:

Alternatively, the compound according to formula (I) may be compounds offormulae (VIc) and (VId) or pharmaceutically acceptable salts thereof:

In an embodiment the compound according to formula (I) may be compoundsof formulae (VIIa) and (VIIb) or pharmaceutically acceptable saltsthereof:

Alternatively, the compound according to formula (I) may be compounds offormulae (VIIc) and (VIId) or pharmaceutically acceptable salts thereof:

In an embodiment the compound according to formula (I) may be compoundsof formulae (VIIIa) and (VIIIb) or pharmaceutically acceptable saltsthereof:

Alternatively, the compound according to formula (I) may be compounds offormulae (VIIIc) and (VIIId) or pharmaceutically acceptable saltsthereof

In an embodiment the compound according to formula (I) may be compoundsof formulae (IXa) and (IXb) or pharmaceutically acceptable salts thereof

Alternatively, the compound according to formula (I) may be compounds offormulae (IXc) and (IXd) or pharmaceutically acceptable salts thereof

For the compounds of formulae (VIa), (VIIa), (VIIIa), (IXa), (VIc),(VIIc), (VIIIc), and (IXc) R⁷ may be as defined elsewhere herein,preferably R⁷ may be selected from: H, fluoro, methyl, methoxy, and—CH₂OH.

In a particular preferred embodiment of the invention R¹ is

Accordingly, the compound according to formula (I) may be a compound offormula (X) or a pharmaceutically acceptable salt thereof:

wherein R^(1A) is selected from C₁₋₂ alkyl or C₁₋₂ haloalkyl and R^(1B)is selected from unsubstituted C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkylsubstituted with OH, C₁₋₄ alkyl substituted with OMe, 5 or 6 memberedheteroaryl, 3 to 6 membered heterocycloalkyl ring, phenyl, or C₃₋₁₀carbocyclic group (such as a 3 to 10 membered cycloalkyl ring); providedthat when R^(1A) is C₁₋₂ alkyl then R^(1B) is not unsubstituted C₁₋₄alkyl.

Preferably, R^(1A) is selected from methyl, difluoromethyl ortrifluoromethyl, and R^(1B) is selected from methyl, ethyl, propyl,trifluoromethyl, difluormethyl, trifluorethyl, —CH₂OH, —CH₂CH₂OH,—CH₂OMe, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyridnyl, phenyl, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; provided that when R^(1A) is not methyl thenR^(1B) is not methyl, ethyl, or propyl. In embodiments, R^(1A) istrifluoromethyl.

Preferably, R^(1A) is selected from methyl or trifluoromethyl, andR^(1B) is selected from methyl, ethyl, propyl, trifluoromethyl,difluormethyl, trifluorethyl, —CH₂OH, —CH₂OMe, pyrrolidinyl,piperidinyl, tetrhydrofuranyl, tetrahydropyranyl, pyridnyl, phenyl,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; provided that whenR^(1A) is not methyl then R^(1B) is not methyl, ethyl, or propyl. Inembodiments, R^(1A) is trifluoromethyl.

The compounds according to formula (I) may be compounds of formula (II)or pharmaceutically acceptable salts thereof:

wherein 0, 1 or 2 of A¹, A², A⁴ and A⁵ are independently selected from Nand the remainder are CR⁷.

In an embodiment compounds according to formula (I) are compounds offormulae (XIIa), (XIIb), (XIIc) and (XIId):

In embodiments the compound according to formula (I) may be compounds offormulae (XIIIa), (XIIIb), (XIIIc), (XIIId), (XIIIe) or (XIIIf) orpharmaceutically acceptable salts thereof:

In an embodiment the compound according to formula (I) may be compoundsof formulae (XIVa), (XIVb), (XIVc) and (XIVd) or pharmaceuticallyacceptable salts thereof:

In an embodiment the compound according to formula (I) may be compoundsof formulae (XVa), (XVb), (XVc) and (XVd) or pharmaceutically acceptablesalts thereof:

In the compounds of formulae (XVa), (XVb), (XVc) and (XVd) R^(C) andR^(D) may be H. In the compounds of formulae (XVa), (XVb), (XVc) and(XVd) R^(E) and R^(F) may be H. In the compounds of formulae (XVa),(XVb), (XVc) and (XVd) R^(C) and R^(D) may be H and R^(E) and R^(F) maybe H.

In an embodiment the compound according to formula (I) may be compoundsof formulae (XVa), (XVb), (XVc) and (XVd) or pharmaceutically acceptablesalts thereof:

In embodiments of the compounds of formula (XVIa), (XVIb), (XVIc) and(XVId) A¹, A², A⁴ and A⁵ are CH, or A¹, A⁴ and A⁵ are CH and A² is CH,or A², A⁴ and A⁵ are CH and A¹ is CF.

In embodiments of the compounds of formula (XVIa), (XVIb), (XVIc) and(XVId) R² represents —NR^(C)R^(D) and R³ represents —C(O)NR^(E)R^(F).Optionally, R^(C) and R^(D) are H and R^(E) and R^(F) are H.

The genus of compounds represented by formula (X), i.e. where R¹ is—CHR^(1A)R^(1B), is an active genus.

Preferred compounds of the invention include:

The compound of formula (I) may be a compound selected from:

Compounds of formula (I) may also be selected from:

Some of the above compounds have one or more chiral centres, for exampleone or two chiral centres. All enantiomers and diastereomers of theabove compounds are contemplated by the invention. Certain chiralcentres are indicated on the compounds above with a * symbol. Thecompounds may have chiral centres in addition to those indicated with a*. In one embodiment the compounds of the invention have the(R)-configuration at the stereocentre. In an alternative embodiment thecompounds of the invention have the (S)-configuration at thestereocentre. Where compounds have two stereocentres the stereocentresmay have (R),(R) configuration, (S),(R) configuration, (R),(S)configuration or (S),(S) configuration. The invention also contemplatesracemic mixtures of these compounds.

The compounds of formula (I) may be compounds selected from:

Any compound described in the examples also forms part of the invention.This includes the compounds falling under the scope of formula (I) andin another aspect any and all novel intermediates in the synthesis ofthe compounds of formula (I).

Less preferred compounds of formula (I) are given below. In certainembodiments the compounds shown below do not form part of the invention.

In another aspect of the invention there is provided a compound of anyformula disclosed herein for use as a medicament.

In another aspect a compound any formula herein is for use in thetreatment of a condition which is modulated by Bruton's tyrosine kinase(BTK). Usually conditions that are modulated by BTK are conditions thatwould be treated by the inhibition of BTK using a compound of thepresent invention. A compound of any formula disclosed herein may be foruse in the treatment of a condition treatable by the inhibition ofBruton's tyrosine kinase (BTK).

BTK inhibition is a novel approach for treating many different humandiseases associated with the inappropriate activation of B-cells,including B-cell proliferative disorders, B-cell malignancies,immunological disease for example, autoimmune, heteroimmune conditions,and inflammatory disorders, or fibrosis. In particular, BTK inhibitionis a novel approach for treating many different human diseasesassociated with the inappropriate activation of B-cells, includingB-cell malignancies, immunological disease for example, autoimmune andinflammatory disorders.

In embodiments the condition treatable by the inhibition of BTK may beselected from: cancer, lymphoma, leukemia, autoimmune diseases,inflammatory disorders, heteroimmune conditions, or fibrosis. Specificconditions treatable by the inhibition of BTK may be selected from:B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer, bone metastasis, follicular lymphoma, chronic lymphocyticlymphoma, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma/,splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma,extranodal marginal zone B-cell lymphoma, nodal marginal zone B-celllymphoma, mediastinal (thymic) large B-cell lymphoma, intravascularlarge B-cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, lymphomatoid granulomatosis, inflammatory boweldisease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome,acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma,vulvodynia, graft versus host disease, transplantation, transfusion,anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis,pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usualinterstitial pneumonitis (UIP), interstitial lung disease, cryptogenicfibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis,fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis(NASH), cholestatic liver disease (e.g., primary biliary cirrhosis(PBC), cirrhosis, alcohol-induced liver fibrosis, biliary duct injury,biliary fibrosis, cholestasis or cholangiopathies. In some embodiments,hepatic or liver fibrosis includes, but is not limited to, hepaticfibrosis associated with alcoholism, viral infection, e.g., hepatitis(e.g., hepatitis C, B or D), autoimmune hepatitis, nonalcoholic fattyliver disease (NAFLD), progressive massive fibrosis, exposure to toxinsor irritants (e.g., alcohol, pharmaceutical drugs and environmentaltoxins), renal fibrosis (e.g., chronic kidney fibrosis), nephropathiesassociated with injury/fibrosis (e.g., chronic nephropathies associatedwith diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of thekidney, glomerular nephritis, focal segmental glomerular sclerosis, IgAnephropathyrenal fibrosis associated with human chronic kidney disease(CKD), chronic progressive nephropathy (CPN), tubulointerstitialfibrosis, ureteral obstruction, chronic uremia, chronic interstitialnephritis, radiation nephropathy, glomerulosclerosis, progressiveglomerulonephrosis (PGN), endothelial/thrombotic microangiopathy injury,HIV-associated nephropathy, or fibrosis associated with exposure to atoxin, an irritant, or a chemotherapeutic agent, fibrosis associatedwith scleroderma; radiation induced gut fibrosis; fibrosis associatedwith a foregut inflammatory disorder such as Barrett's esophagus andchronic gastritis, and/or fibrosis associated with a hindgutinflammatory disorder, such as inflammatory bowel disease (IBD),ulcerative colitis and Crohn's disease, age-related maculardegeneration, diabetic retinopathy, retinopathy of prematurity andneovascular glaucoma.

B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer, bone metastasis, chronic lymphocytic lymphoma, B-cellprolymphocyte leukemia, lymphoplasmacytic lymphoma/, splenic marginalzone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginalzone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal(thymic) large B-cell lymphoma, intravascular large B-cell lymphoma,primary effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoidgranulomatosis are examples of cancer, lymphoma and leukemia treatableby BTK inhibition.

B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer and bone metastasis are examples of cancer, lymphoma andleukemia treatable by BTK inhibition.

Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, andvulvodynia, asthma, appendicitis, blepharitis, bronchiolitis,bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, vulvitis graft versus hostdisease, transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopicdermatitis are examples of immunological diseases treatable by BTKinhibition.

Arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis are examplesof an inflammatory disorder treatable by BTK inhibition.

Lupus and Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease, Sjogren's syndrome, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia are examples of an autoimmunedisease treatable by BTK inhibition.

Graft versus host disease, transplantation, transfusion, anaphylaxis,allergy, type I hypersensitivity, allergic conjunctivitis, allergicrhinitis, and atopic dermatitis are examples of a heteroimmune conditiontreatable by BTK inhibition.

Pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usualinterstitial pneumonitis (UIP), interstitial lung disease, cryptogenicfibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis,fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis(NASH), cholestatic liver disease (e.g., primary biliary cirrhosis(PBC), cirrhosis, alcohol-induced liver fibrosis, biliary duct injury,biliary fibrosis, cholestasis or cholangiopathies. In some embodiments,hepatic or liver fibrosis includes, but is not limited to, hepaticfibrosis associated with alcoholism, viral infection, e.g., hepatitis(e.g., hepatitis C, B or D), autoimmune hepatitis, nonalcoholic fattyliver disease (NAFLD), progressive massive fibrosis, exposure to toxinsor irritants (e.g. alcohol, pharmaceutical drugs and environmentaltoxins), renal fibrosis (e.g. chronic kidney fibrosis), nephropathiesassociated with injury/fibrosis (e.g., chronic nephropathies associatedwith diabetes (e.g. diabetic nephropathy)), lupus, scleroderma of thekidney, glomerular nephritis, focal segmental glomerular sclerosis, IgAnephropathyrenal fibrosis associated with human chronic kidney disease(CKD), chronic progressive nephropathy (CPN), tubulointerstitialfibrosis, ureteral obstruction, chronic uremia, chronic interstitialnephritis, radiation nephropathy, glomerulosclerosis, progressiveglomerulonephrosis (PGN), endothelial/thrombotic microangiopathy injury,HIV-associated nephropathy, or fibrosis associated with exposure to atoxin, an irritant, a chemotherapeutic agent, fibrosis associated withscleroderma; radiation induced gut fibrosis; fibrosis associated with aforegut inflammatory disorder such as Barrett's esophagus and chronicgastritis, and/or fibrosis associated with a hindgut inflammatorydisorder, such as inflammatory bowel disease (IBD), ulcerative colitisand Crohn's disease, age-related macular degeneration, diabeticretinopathy, retinopathy of prematurity and neovascular glaucoma areexamples of fibrosis treatable by BTK inhibition.

Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease and lupus are examples ofimmunological diseases treatable by BTK inhibition. Arthritis is anexample of an inflammatory disorder treatable by BTK inhibition. Lupusand Sjögren's syndrome is an example of an autoimmune disease treatableby BTK inhibition.

Any of the conditions disclosed above as being treatable by BTKinhibition may be treated by a compound of the invention, or may betreated in a method comprising administering a compound of theinvention, or may be treated by a medicament manufactured through theuse of a compound of the present invention.

In embodiments, a compound of the invention may be for use in thetreatment of: cancer, lymphoma, leukemia, immunological diseases,autoimmune diseases and inflammatory disorders. The compound of theinvention may be for use in the treatment of specific conditionsselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia,multiple myeloma, bone cancer, bone metastasis, arthritis, multiplesclerosis osteoporosis, irritable bowel syndrome, inflammatory boweldisease, Crohn's disease, Sjögren's syndrome and lupus. The compoundsmay also be used for the treatment of disorders associated with renaltransplant.

In an embodiment the compound of the invention may be for use in thetreatment of specific conditions selected from: B-cell malignancy,B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyteleukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle celllymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkinlymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, lupus andarthritis.

In an aspect of the invention there is provided a method of treatment ofa condition which is modulated by Bruton's tyrosine kinase, wherein themethod comprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof.

The method of treatment may be a method of treating a conditiontreatable by the inhibition of Bruton's tyrosine kinase.

The invention also provides a method of treating a condition selectedfrom: cancer, lymphoma, leukemia, immunological diseases autoimmunediseases and inflammatory disorders, wherein the method comprisesadministering a therapeutic amount of a compound of the invention, to apatient in need thereof. The invention also provides a method oftreating a specific condition selected from: B-cell malignancy, B-celllymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia,non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma,follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma,Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bonemetastasis, arthritis, multiple sclerosis osteoporosis, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease, Sjögren'ssyndrome and lupus, wherein the method comprises administering atherapeutic amount of a compound of any formula disclosed herein, to apatient in need thereof. The method may also treat disorders associatedwith renal transplant.

In an embodiment the method may be for treating a specific conditionselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia,multiple myeloma, arthritis and lupus.

In another aspect of the invention there is provided a pharmaceuticalcomposition, wherein the composition comprises a compound of theinvention and pharmaceutically acceptable excipients.

In an embodiment the pharmaceutical composition may be a combinationproduct comprising an additional pharmaceutically active agent. Theadditional pharmaceutically active agent may be an anti-tumor agentdescribed below

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

The term “halo” refers to one of the halogens, group 17 of the periodictable. In particular the term refers to fluorine, chlorine, bromine andiodine. Preferably, the term refers to fluorine or chlorine.

The term “alkyl” refers to a linear or branched hydrocarbon chain. Forexample, the terms “C₁₋₈ alkyl” or “C₁₋₆ alkyl” refer to a linear orbranched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms or1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, for example methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andn-hexyl. Alkylene groups may likewise be linear or branched and may havetwo places of attachment to the remainder of the molecule. Furthermore,an alkylene group may, for example, correspond to one of those alkylgroups listed in this paragraph. The alkyl and alkylene groups may beunsubstituted or substituted by one or more substituents. Possiblesubstituents are described below. Substituents for the alkyl group maybe halogen, e.g. fluorine, chlorine, bromine and iodine, OH, ═O, or C₁₋₆alkoxy.

The term “alkoxy” refers to an alkyl group which is attached to amolecule via oxygen. This includes moieties where the alkyl part may belinear or branched. For example, the term “C₁₋₆ alkoxy” refers to analkyl group which is attached to a molecule via oxygen containing 1, 2,3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.The alkyl part of the alkoxy group may be unsubstituted or substitutedby one or more substituents. Possible substituents are described below.Substituents for the alkyl group may be halogen, e.g. fluorine,chlorine, bromine and iodine, OH, C₁₋₆ alkoxy.

The term “alkyl ether” refers to a linear or branched alkyl chain thatis interrupted by a single oxygen atom to provide an ether. For example,the terms “C₂₋₆ alkyl ether” or “C₂₋₄ alkyl ether” refer to a linear orbranched hydrocarbon chain containing 2, 3, 4, 5 or 6 carbon atoms or 2,3, or 4 carbon atoms with a single oxygen atom within the chain, forexample —CH₂OCH₃, —(CH₂)₂OCH₃, —(CH₂)₃OCH₃, —CH₂OCH₂CH₃, —CH₂O(CH₂)₂CH₃or —(CH₂)₂O(CH₂)₂CH₃.

The term “haloalkyl” refers to a hydrocarbon chain substituted with atleast one halogen atom independently chosen at each occurrence, forexample fluorine, chlorine, bromine and iodine. The halogen atom may bepresent at any position on the hydrocarbon chain. For example, “C₁₋₆haloalkyl” refers to a hydrocarbon chain substituted with at least onehalogen atom containing 1, 2, 3, 4, 5 or 6 carbon atoms, for examplechloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g.1-chloromethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g.1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl,trichloropropyl, fluoropropyl, trifluoropropyl.

The term “alkenyl” refers to a branched or linear hydrocarbon chaincontaining at least one double bond. For example, the term “C₂₋₆alkenyl” refers to a branched or linear hydrocarbon chain containing atleast one double bond having 2, 3, 4, 5 or 6 carbon atoms. The doublebond(s) may be present as the E or Z isomer. The double bond may be atany possible position of the hydrocarbon chain. For example, the “C₂₋₆alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl,pentadienyl, hexenyl and hexadienyl.

The term “alkynyl” refers to a branded or linear hydrocarbon chaincontaining at least one triple bond. For example, the term “C₂₋₆alkynyl” refers to a branded or linear hydrocarbon chain containing atleast one triple bond having 2, 3, 4, 5 or 6 carbon atoms. The triplebond may be at any possible position of the hydrocarbon chain. Forexample, the “C₂₋₆ alkynyl” may be ethynyl, propynyl, butynyl, pentynyland hexynyl.

The term “heteroalkyl” refers to a branched or linear hydrocarbon chainat least one heteroatom selected from N, O and S positioned between anycarbon in the chain or at an end of the chain. For example, the term“C₁₋₆ heteroalkyl” refers to a branded or linear hydrocarbon chaincontaining 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatomselected from N, O and S positioned between any carbon in the chain orat an end of the chain. For example, the hydrocarbon chain may containone or two heteroatoms. The C₁₋₆ heteroalkyl may be bonded to the restof the molecule through a carbon or a heteroatom. For example, the “C₁₋₆heteroalkyl” may be C₁₋₆ N-alkyl, C₁₋₆ N,N-alkyl, or C₁₋₆ O-alkyl.

The term “carbocyclic” refers to a saturated or unsaturated carboncontaining ring system. A “carbocyclic” system may be monocyclic or afused polycyclic ring system, for example, bicyclic or tricyclic. A“carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example,3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in apolycyclic system. “Carbocyclic” encompasses cycloalkyl moieties,cycloalkenyl moieties, aryl ring systems and fused ring systemsincluding an aromatic portion.

The term “heterocyclic” refers to a saturated or unsaturated ring systemcontaining at least one heteroatom selected from N, O or S. A“heterocyclic” system may contain 1, 2, 3 or 4 heteroatoms, for example1 or 2. A “heterocyclic” system may be monocyclic or a fused polycyclicring system, for example, bicyclic or tricyclic. A “heterocyclic” moietymay contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atomsin a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.“Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenylmoieties and heteroaromatic moieties. For example, the heterocyclicgroup may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran,pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,thiomorpholine, piperazine, and tetrahydropyran.

The term “cycloalkyl” refers to a saturated hydrocarbon ring system. The“cycloalkyl” group may be denoted as a “C₃₋₁₀ cycloalkyl” containing 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring system may be a singlering or a bi-cyclic or tri-cyclic ring system. For example, the“cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclohexyl, cycloheptyl and cyclooctyl.

The term “cycloalkenyl” refers to an unsaturated hydrocarbon ring systemthat is not aromatic. The “cycloalkenyl” group may be denoted as a“C₃₋₁₀ cycloalkenyl”. A “C₃₋₁₀ cycloalkenyl” is a ring system containing3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring may contain more thanone double bond provided that the ring system is not aromatic. The ringsystem may be a single ring or a bi-cyclic or tri-cyclic ring system.For example, the “cycloalkenyl” may be cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly,cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

The term “heterocycloalkyl” refers to a saturated hydrocarbon ringsystem with at least one heteroatom within the ring selected from N, Oand S. The “heterocycloalkyl” group may be denoted as a “C₃₋₁₀heterocycloalkyl”. A “C₃₋₁₀ heterocycloalkyl” is a ring systemcontaining 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being aheteroatom. For example there may be 1, 2 or 3 heteroatoms, optionally 1or 2. The “heterocycloalkyl” group may also be denoted as a “3 to 10membered heterocycloalkyl” which is also a ring system containing 3, 4,5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. The ringsystem may be a single ring or a bi-cyclic or tri-cyclic ring system.Where the ring system is bicyclic one of the rings may be an aromaticring, for example as in indane. The “heterocycloalkyl” may be bonded tothe rest of the molecule through any carbon atom or heteroatom. The“heterocycloalkyl” may have one or more, e.g. one or two, bonds to therest of the molecule: these bonds may be through any of the atoms in thering. For example, the “heterocycloalkyl” may be oxirane, aziridine,azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine,succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine,tetrahydropyran, and indane.

The term “heterocycloalkenyl” refers to an unsaturated hydrocarbon ringsystem, that is not aromatic, having at least one heteroatom within thering selected from N, O and S. The “heterocycloalkenyl” group may bedenoted as a “C₃₋₁₀ heterocycloalkenyl”. A “C₃₋₁₀ heterocycloalkenyl” isa ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least onebeing a heteroatom. For example there may be 1, 2 or 3 heteroatoms,optionally 1 or 2. The “heterocycloalkenyl” group may also be denoted asa “3 to 10 membered heterocycloalkenyl” which is also a ring systemcontaining 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being aheteroatom. The ring system may be a single ring or a bi-cyclic ortri-cyclic ring system. Where the ring system is bicyclic one of therings may be an aromatic ring, for example as in indoline anddihydrobenzofuran. The “heterocycloalkenyl” may be bonded to the rest ofthe molecule through any carbon atom or heteroatom. The“heterocycloalkenyl” may have one or more, e.g. one or two, bonds to therest of the molecule: these bonds may be through any of the atoms in thering. For example, the “C₃₋₈ heterocycloalkenyl” may betetrahydropyridine, dihydropyran, dihydrofuran, pyrroline,dihydrobenzofuran, dihydrobenzothiophene and indoline.

The term “aromatic” when applied to a substituent as a whole means asingle ring or polycyclic ring system with 4n+2 electrons in aconjugated π system within the ring or ring system where all atomscontributing to the conjugated π system are in the same plane.

The term “aryl” refers to an aromatic hydrocarbon ring system. The ringsystem has 4n+2 electrons in a conjugated π system within a ring whereall atoms contributing to the conjugated π system are in the same plane.The ring system may be a single ring or a bi-cyclic or tri-cyclic ringsystem. For example, the “aryl” may be phenyl and naphthyl. The arylsystem itself may be substituted with other groups.

The term “heteroaryl” refers to an aromatic hydrocarbon ring system withat least one heteroatom within a single ring or within a fused ringsystem, selected from O, N and S. The ring or ring system has 4n+2electrons in a conjugated π system where all atoms contributing to theconjugated π system are in the same plane. The ring system may be asingle ring or a bi-cyclic or tri-cyclic ring system. For example, the“heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrol,benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

The term “alkaryl” refers to an aryl group, as defined above, bonded toa C₁₋₄ alkyl, where the C₁₋₄ alkyl group provides attachment to theremainder of the molecule.

The term “alkheteroaryl” refers to a heteroaryl group, as defined above,bonded to a C₁₋₄ alkyl, where the alkyl group provides attachment to theremainder of the molecule.

The term “halogen” herein includes reference to F, Cl, Br and I. Halogenmay be Cl. Halogen may be F.

A bond terminating in a “

” represents that the bond is connected to another atom that is notshown in the structure. A bond terminating inside a cyclic structure andnot terminating at an atom of the ring structure represents that thebond may be connected to any of the atoms in the ring structure whereallowed by valency.

Where a moiety is substituted, it may be substituted at any point on themoiety where chemically possible and consistent with atomic valencyrequirements. The moiety may be substituted by one or more substituents,e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituentson a group. Where there are two or more substituents, the substituentsmay be the same or different. The substituent(s) may be selected from:OH, NHR⁹, amidino, guanidino, hydroxyguanidino, formamidino,isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo,sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl or alkaryl. Where the group to be substituted is an alkylgroup the substituent may be ═O. Where the moiety is substituted withtwo or more substituents and two of the substituents are adjacent theadjacent substituents may form a C₄₋₈ ring along with the atoms of themoiety on which the substituents are substituted, wherein the C₄₋₈ ringis a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5,6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.

If chemically possible to do so, a cyclic substituent may be substitutedon a group so as to form a spiro-cycle.

Substituents are only present at positions where they are chemicallypossible, the person skilled in the art being able to decide (eitherexperimentally or theoretically) without inappropriate effort whichsubstitutions are chemically possible and which are not.

Ortho, meta and para substitution are well understood terms in the art.For the absence of doubt, “ortho” substitution is a substitution patternwhere adjacent carbons possess a substituent, whether a simple group,for example the fluoro group in the example below, or other portions ofthe molecule, as indicated by the bond ending in “

”,

“Meta” substitution is a substitution pattern where two substituents areon carbons one carbon removed from each other, i.e with a single carbonatom between the substituted carbons. In other words there is asubstituent on the second atom away from the atom with anothersubstituent. For example the groups below are meta substituted.

“Para” substitution is a substitution pattern where two substituents areon carbons two carbons removed from each other, i.e with two carbonatoms between the substituted carbons. In other words there is asubstituent on the third atom away from the atom with anothersubstituent. For example the groups below are para substituted.

By “acyl” is meant an organic radical derived from, for example, anorganic acid by the removal of the hydroxyl group, e.g. a radical havingthe formula R—C(O)—, where R may be selected from H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C₁₋₃ alkyl.In one embodiment acyl is alkyl-carbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, acetyl, propionyl and butyryl.A particular acyl group is acetyl.

In embodiments where there is a single enantiomer of the compounds ofthe invention, the compounds of the invention may have an enantiomericpurity of at least about 90% enantiomeric excess (ee), at least about95% enantiomeric excess (ee), at least about 98% enantiomeric excess(ee), at least about 99% enantiomeric excess (ee), or 100% enantiomericexcess (ee). In embodiments where there is a mixture of enantiomers ofthe compounds of the invention, the compounds of the invention may be aracemic mixture or any other mixture of enantiomers, for example thecompounds of the invention may have an enantiomeric purity of at leastabout 50% enantiomeric excess (ee), at least about 60% enantiomericexcess (ee), at least about 70% enantiomeric excess (ee), at least about80% enantiomeric excess (ee), at least about 90% enantiomeric excess(ee), or at least about 95% enantiomeric excess (ee).

Throughout the description the disclosure of a compound also encompassespharmaceutically acceptable salts, solvates and stereoisomers thereof.Where a compound has a stereocentre, both (R) and (S) stereoisomers arecontemplated by the invention, equally mixtures of stereoisomers or aracemic mixture are completed by the present application. Where acompound of the invention has two or more stereocentres any combinationof (R) and (S) stereoisomers is contemplated. The combination of (R) and(S) stereoisomers may result in a diastereomeric mixture or a singlediastereoisomer. The compounds of the invention may be present as asingle stereoisomer or may be mixtures of stereoisomers, for exampleracemic mixtures and other enantiomeric mixtures, and diasteroemericmixtures. Where the mixture is a mixture of enantiomers the enantiomericexcess may be any of those disclosed above. Where the compound is asingle stereoisomer the compounds may still contain otherdiasteroisomers or enantiomers as impurities. Hence a singlestereoisomer does not necessarily have an enantiomeric excess (e.e.) ordiastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. ofabout at least 85%

The invention contemplates pharmaceutically acceptable salts of thecompounds of formula (I). These may include the acid addition and basesalts of the compounds. These may be acid addition and base salts of thecompounds. In addition the invention contemplates solvates of thecompounds. These may be hydrates or other solvated forms of thecompound.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methyl sulfate, naphthylate,1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulfate and hemicalciumsalts. For a review on suitable salts, see “Handbook of PharmaceuticalSalts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid orbase;(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of formula (I) or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or(iii) by converting one salt of the compound of formula (I) to anotherby reaction with an appropriate acid or base or by means of a suitableion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of any formula includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of a number of formulaas herein defined, including all polymorphs and crystal habits thereof,prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of the invention.

Before purification, the compounds of the present invention may exist asa mixture of enantiomers depending on the synthetic procedure used. Theenantiomers can be separated by conventional techniques known in theart. Thus the invention covers individual enantiomers as well asmixtures thereof.

For some of the steps of the process of preparation of the compounds offormula (I), it may be necessary to protect potential reactive functionsthat are not wished to react, and to cleave said protecting groups inconsequence. In such a case, any compatible protecting radical can beused. In particular methods of protection and deprotection such as thosedescribed by T. W. GREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protectinggroups, Georg Thieme Verlag, 1994), can be used. All of the abovereactions and the preparations of novel starting materials used in thepreceding methods are conventional and appropriate reagents and reactionconditions for their performance or preparation as well as proceduresfor isolating the desired products will be well-known to those skilledin the art with reference to literature precedents and the examples andpreparations hereto.

Also, the compounds of the present invention as well as intermediatesfor the preparation thereof can be purified according to variouswell-known methods, such as for example crystallization orchromatography.

The method of treatment or the compound for use in the treatment ofcancer, lymphoma, leukemia or immunological diseases as definedhereinbefore may be applied as a sole therapy or be a combinationtherapy with an additional active agent.

The method of treatment or the compound for use in the treatment ofcancer, lymphoma or leukemia may involve, in addition to the compound ofthe invention, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof,such as alkylating agents (for example cis-platin, oxaliplatin,carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan,chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites(for example gemcitabine and antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed,cytosine arabinoside, and hydroxyurea); antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere and polokinase inhibitors); proteasome inhibitors, for examplecarfilzomib and bortezomib; interferon therapy; and topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, mitoxantrone and camptothecin);(ii) cytostatic agents such as antiestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents, for example dasatinib and bosutinib(SKI-606), and metalloproteinase inhibitors, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies,for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab,tyrosine kinase inhibitors, for example inhibitors of the epidermalgrowth factor family (for example EGFR family tyrosine kinase inhibitorssuch as gefitinib, erlotinib and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; modulators of protein regulators of cellapoptosis (for example Bcl-2 inhibitors); inhibitors of theplatelet-derived growth factor family such as imatinib and/or nilotinib(AMN107); inhibitors of serine/threonine kinases (for example Ras/Rafsignalling inhibitors such as farnesyl transferase inhibitors, forexample sorafenib, tipifamib and lonafarnib), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitorsand cyclin dependent kinase inhibitors such as CDK2 and/or CDK4inhibitors;(v) anti angiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™);thalidomide; lenalidomide; and for example, a VEGF receptor tyrosinekinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib andpazopanib;(vi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;(vii) immunotherapy approaches, including for example antibody therapysuch as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) andofatumumab; interferons such as interferon α; interleukins such as IL-2(aldesleukin); interleukin inhibitors for example IRAK4 inhibitors;cancer vaccines including prophylactic and treatment vaccines such asHPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T(Provenge); and tolyl-like receptor modulators for example TLR-7 orTLR-9 agonists; and(viii) cytotoxic agents for example fludaribine (fludara), cladribine,pentostatin (Nipent™);(ix) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(x) targeted therapies, for example PI3Kd inhibitors, for exampleidelalisib and perifosine.

The method of treatment or the compound for use in the treatment ofimmunological diseases may involve, in addition to the compound of theinvention, additional active agents. The additional active agents may beone or more active agents used to treat the condition being treated bythe compound of formula (I) and additional active agent. The additionalactive agents may include one or more of the following active agents:—

(i) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g.infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and5-HT_(2A) agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2,lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);(iii) anti-inflammatory drugs, for example non-steroidalanti-inflammatory drugs;(iv) dihydrofolate reductase inhibitors/antifolates, for examplemethotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim,pemetrexed, ralitrexed and pralatrexate; and(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimuspimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan,Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan)and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril,Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril,Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril,Trandolapril), phosphate-containing agents (e.g. Fosinopril),casokinins, lactokinins and lactotripeptides.

Such combination treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within a therapeutically effective dosage range describedhereinbefore and the other pharmaceutically-active agent within itsapproved dosage range.

According to a further aspect of the invention there is provided apharmaceutical product comprising a compound of formula (I), or apharmaceutically acceptable salt thereof as defined hereinbefore and anadditional active agent. The additional active agent may be ananti-tumour agent as defined hereinbefore for the combination treatmentof a condition modulated by BTK.

According to a further aspect of the invention there is provided amethod of treatment a condition modulated by BTK comprisingadministering a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereofsimultaneously, sequentially or separately with an additional anti-tumoragent, as defined hereinbefore, to a patient in need thereof.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use simultaneously, sequentially or separately with an additionalanti-tumour agent as defined hereinbefore, in the treatment of acondition modulated by BTK.

According to another aspect of the invention there is provided a use ofthe compound of formula (I) in combination with an anti-tumor agent ashereinbefore described. The compound of formula (I) may be usedsimultaneously, sequentially or separately with the additionalanti-tumor agent The use may be in a single combination productcomprising the compound of formula (I) and the anti-tumor agent.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

The condition modulated by BTK described above may be cancer, leukemiaor cancer. More specifically the condition modulated by BTK may beselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemiaand multiple myeloma.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous. Thus, compounds ofthe invention intended for pharmaceutical use may be administered ascrystalline or amorphous products. They may be obtained, for example, assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, or spray drying, or evaporative drying.Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosageadministered will, of course, vary with the compound employed, the modeof administration, the treatment desired and the disorder indicated. Forexample, if the compound of the invention is administered orally, thenthe daily dosage of the compound of the invention may be in the rangefrom 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligramsper kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable saltthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the compounds of theinvention, or pharmaceutically acceptable salt thereof, is inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of the compounds of theinvention, the pharmaceutical composition which is used to administerthe compounds of the invention will preferably comprise from 0.05 to 99%w (percent by weight) compounds of the invention, more preferably from0.05 to 80% w compounds of the invention, still more preferably from0.10 to 70% w compounds of the invention, and even more preferably from0.10 to 50% w compounds of the invention, all percentages by weightbeing based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe skin) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); by rectal administration in the form ofsuppositories; or by inhalation in the form of an aerosol.

For oral administration the compounds of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compounds of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules. Liquid preparations for oralapplication may be in the form of syrups or suspensions, for example,solutions containing the compound of the invention, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquid preparations may contain colouring agents,flavouring agents, sweetening agents (such as saccharine), preservativeagents and/or carboxymethylcellulose as a thickening agent or otherexcipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of theinvention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well-known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds ofthe invention are expected to differ depending on the formulation andclinical indication, age, and co-morbid medical conditions of thepatient. The standard duration of treatment with compounds of theinvention is expected to vary between one and seven days for mostclinical indications. It may be necessary to extend the duration oftreatment beyond seven days in instances of recurrent infections orinfections associated with tissues or implanted materials to which thereis poor blood supply including bones/joints, respiratory tract,endocardium, and dental tissues.

EXAMPLES AND SYNTHESIS

As used herein the following terms have the meanings given: “Boc” refersto tert-butoxycarbonyl; “DCM” refers to dichloromethane; “DIPEA” refersto N,N-Diisopropylethylamine; “EtOAc” refers to ethyl acetate; “LCMS”refers to liquid chromatography/mass spectrometry; “MIM” refers tomonoisotopic mass; “min” refers to minutes; “DMF” refers toN,N-dimethylformamide; “Pet. Ether” refers to petroleum ether; “TLC”refers to thin layer chromatography; “Rf” refers to Retention factor;“RT” refers to RT; “SCX” refers to strong cation exchange; “TEA” refersto triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers totetrahydrofuran; and “TBME” refers to tert-butyl methyl ether.

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at RT unless otherwise stated.

Compound identity and purity confirmations were performed by LCMS UVusing a Waters Acquity SQ Detector 2 (ACQ-SQD2 #LCA081). The diode arraydetector wavelength was 254 nM and the MS was in positive and negativeelectrospray mode (m/z: 150-800). A 2 μL aliquot was injected onto aguard column (0.2 μm×2 mm filters) and UPLC column (C18, 50×2.1 mm, <2μm) in sequence maintained at 40° C. The samples were eluted at a flowrate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v)Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile)according to the gradients outlined in Table 1 below. Retention times RTare reported in minutes.

TABLE 1 Time (min) % A % B Long Acidic 0 95 5 1.1 95 5 6.1 5 95 7 5 957.5 95 5 8 95 5 Short Acidic 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5

Compound identity confirmations were also performed by LCMS UV using aWaters Alliance 2695 micromass ZQ (K98SM4 512M-LAA434). The diode arraydetector wavelength was 254 nM and the MS was in positive and negativeelectrospray mode (<m/z: 150-650). A 10 μL aliquot was injected onto anHPLC column (C18, 75×4.6 mm, 2.5 μm) at RT which was controlled at 19°C. The samples were eluted at a flow rate of 0.9 mL/min with a mobilephase system composed of A (0.1% (v/v) Formic Acid in 95:5 (v/v) Water:Acetonitrile) and B (0.1% (v/v) Formic Acid in 95:5 (v/v) Acetonitrile:Water) according to the gradients outlined in Table 2 below. Retentiontimes RT are reported in minutes.

TABLE 2 Method 1 Time (min) % A % B 0 100 0 5.5 0 100 6.0 5 100 6.5 1000 7 100 0

Compound identity confirmations were also performed by analyticalSupercritical Fluid Chromatography (SFC) using an Agilent 1260analytical SFC (SFC-A). A 10 μL aliquot was injected onto an HPLC column(C18, 75×4.6 mm, 2.5 μm) at RT which was controlled at 19° C. Thesamples were eluted at a flow rate of 3 mL/min with a mobile phasesystem composed of A for CO₂ and B for methanol (0.05% DEA, V/V) elutingwith a gradient of Phase B from 5% to 40% in 3.6 min.

NMR was also used to characterise final compounds. NMR spectra wereobtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe. Optionally,compound Rf values on silica thin layer chromatography (TLC) plates weremeasured.

Compound purification was performed by flash column chromatography onsilica or by preparative LCMS. LCMS purification was performed using aWaters 3100 Mass detector in positive and negative electrospray mode(m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were elutedat a flow rate of 20 mL/min on a XBridge™ prep C18 5 μM OBD 19×100 mmcolumn with a mobile phase system composed of A (0.1% (v/v) Formic Acidin Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according tothe gradient outlined in Table 3 below.

TABLE 3 Time (min) % A % B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 9090 15 90 90

Compound purification was also performed by preparative SupercriticalFluid Chromatography (SFC). SFC purification was performed using aWaters 80Q preparative SFC (SFC-B). Samples were eluted at a flow rateof 50 g/min on a ChiralPak OJ-H column, 250×30 mm I.D. in 5 μm particlesize with a mobile phase system composed of A for CO₂ and B for Methanol(0.1% NH₃H₂O) under isocratic elution (25% phase B).

Chemical names in this document were generated using mol2nam—Structureto Name Conversion by OpenEye Scientific Software. Starting materialswere purchased from commercial sources or synthesised according toliterature procedures.

General Schemes

Compounds of the invention may be produced by following either of thegeneral schemes shown below, either General Scheme1 or General Scheme 2.

In an aspect of the invention there is provided a compound of formula(A):

-   wherein R⁶ is as defined elsewhere herein, optionally wherein R⁶ is    a substituted phenyl or a substituted or unsubstituted 5 or 6    membered heteroaryl ring, wherein, when substituted, R⁶ contains    from 1 to 5 substituents independently selected at each occurrence    from: halo, —OR^(I), —NR^(I)R^(J), —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,    and C₁₋₆ alkyl substituted with —OR^(I);-   Y is a halo group, for example fluoro; and-   Z is a metal ion, for example a group 1 metal such as potassium or    sodium.

In the above aspect of the invention R6 is preferably substituted by amethoxy group and 0 to 4 additional substituents independently selectedat each occurrence from: halo, —OR^(I), —NR^(I)R^(J), —CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and C₁₋₆ alkyl substituted with —OR^(I).

In a preferred embodiment the compound according to formula (A) is acompound according to formula (B) or (C):

General Procedures

General Procedure A

To a suspension of 4-(aminomethyl)phenyl]boronic acid hydrochloride (1.1eq.) and the corresponding benzoic acid (1.0 eq.) in anhydrous THF (0.49M), under a nitrogen atmosphere, was added successively,N,N-diisopropylethylamine (5.0 eq.) and a propylphosphonic anhydridesolution (50 wt % in EtOAc) (1.5 eq.). The reaction mixture was heatedunder reflux at 70° C. for 14 h with stirring. The mixture was dilutedwith water and DCM, then partitioned. The aqueous layer was extractedwith DCM (×2). The combined organic extracts were filtered over a phaseseparator and concentrated under reduced pressure to afford the desiredboronic acid. No further purification was attempted and the product wasused directly in the next step.

General Procedure B

To a suspension of 4-(aminomethyl)phenyl]boronic acid hydrochloride (1.0eq.) and DIPEA (3.0 eq.) in anhydrous THF (0.2 M) under a nitrogenatmosphere was added a solution of the corresponding benzoyl chloridederivative (1.1 eq.) in anhydrous THF (0.2 M). The reaction mixture wasstirred for 16 h at RT, quenched with a saturated aqueous solution ofammonium chloride and then extracted into ethyl acetate (×3). Thecombined organics were washed with brine, dried over Na₂SO₄ and filteredthen concentrated under reduced pressure to afford the desired boronicacid derivative. No further purification was attempted and the productwas used directly in the next step.

General Procedure C

A mixture of halide (1.0 eq.), boronic acid or pinacol ester (1.5 eq.)and potassium carbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M)was degassed by bubbling nitrogen through it for 25 min.1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq.) was added and the mixture wasdegassed again by bubbling nitrogen through it for 30 min. The mixturewas then heated at 120° C. for 14 h. The reaction mixture was filteredover Celite®. The cake was rinsed with DCM. Water was added to thefiltrate and the layers were partitioned. The aqueous layer wasextracted with DCM (×2). The combined organic extracts were filteredover phase separator and then concentrated under reduced pressure togive a dark solid. Further purification by flash column chromatographyon silica gel gave the desired compound.

General Procedure D

A mixture of halide (1.0 eq.), boronic acid or pinacol ester (1.5 eq.)and potassium carbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M)was degassed by bubbling nitrogen through it for 15 min.1,1′-bis(diphenylphosphino)ferrocene-palladium(II) di chloridedichloromethane complex (0.05 eq.) was added and the mixture wasdegassed again by bubbling nitrogen through it for 15 min. The mixturewas then heated under microwave irradiation at 120-140° C. for 60-90min. The reaction mixture was either purified by SCX SPE cartridge andused as such or purified using the following procedure, unless statedused crude. The mixture was filtered through a pad of Celite®. The cakewas rinsed with DCM. Water was added to the filtrate and the layers werepartitioned. The aqueous layer was extracted with DCM (×2). The combinedorganic extracts were filtered over phase separator and thenconcentrated under reduced pressure to give a dark solid. Furtherpurification by flash column chromatography gave the desired compound.

General Procedure E

To a solution of ketone (1.0 eq.) in MeOH (0.2 M) were added thecorresponding hydrazine (1.05 eq.) and the reaction was stirred for 15 hat RT. Volatiles were removed under reduced pressure to provide crudeBoc-hydrazone derivative.

General Procedure F

A methanol solution of Boc-hydrazone derivative (1.00 eq.) was treatedwith 10% palladium on carbon (0.02 eq), acetic acid (0.01 eq.) andpurged with H₂. The solution was stirred under H₂ (1 atm) overnightbefore being filtered through Celite®. The filtrate was concentratedunder reduced to provide the corresponding Boc-protected hydrazine.

General Procedure G

To a solution of Boc-protected hydrazine (1.0 eq.) in MeOH (0.5 M) wasadded 4 N HCI in 1,4-dioxane (8.0 eq.) and the reaction was stirred atRT for 5 h. Diethyl ether was added and a precipitate formed which wascollected by filtration to provide the desired hydrazine intermediate.Alternatively, the mixture was concentrated under reduced pressure andused as such.

General Procedure H

To a solution of 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(1.0 eq.) and TEA (3.0 eq.) in EtOH (0.6 M) was added the correspondinghydrazine derivative (1.2 eq.) and the reaction was then stirred for2-14 h at 100° C. Volatiles were removed under reduced pressure. Asaturated aqueous solution of ammonium chloride and ethyl acetate wereadded to the residue, the organic layer was separated, washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. Further purification by flash column chromatography onsilica gel afforded the desired compound.

General Procedure I

To a stirred solution of alcohol (1.0 eq.) in DCM (0.9 M), cooled at 0°C. under a nitrogen atmosphere, was added triethylamine (1.1 eq.). Theresulting solution was stirred for 10 min before adding dropwisemethanesulfonyl chloride (1.1 eq.). The reaction mixture was stirred at0° C. for 1 h, quenched with water, and extracted with DCM (×2). Thecombined organic extracts were filtered over a phase separator andconcentrated under reduced pressure to afford the desired mesylatedproduct.

General Procedure J

Hydrochloric acid (1 M, 3.0 eq.) was added to a suspension of1,3-dioxolane derivative (1.0 eq.) in THF (1 M), cooled at 0° C. Thereaction mixture was allowed to return to RT and stirred for 14 h. Themixture was then carefully basified with a saturated solution of sodiumcarbonate and the aqueous layer was extracted with DCM (×3). Thecombined organic extracts were filtered over a phase separator andconcentrated under reduced pressure to afford crude carbonyl.

General Procedure K

A mixture of halide derivative (1.0 eq.), Molander salt (1.0 eq.),cesium carbonate (3.0 eq.) and XPhos (0.1 eq) in THF and water (10:1,0.06 M) was degassed by bubbling nitrogen through it for 15 min.Palladium acetate (0.05 eq.) was then added and the mixture was degassedagain by bubbling nitrogen through it for 5 min. The mixture was thenheated to 85° C. for 16 h, filtered over Celite®. The cake was rinsedwith DCM. Water was added to the filtrate and the layers werepartitioned. The aqueous layer was extracted with DCM (×2). The combinedorganic extracts were filtered over phase separator and thenconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel gave the desired compound.

General Procedure L

To a solution of nitrile derivative (1.0 eq.) in EtOH/water (2:1, 0.8 M)hydrido(dimethylphosphinous acid kP) [hydrogenbis(dimethylphosphinito-kP)]platinum (II) (0.07 g, 0.163 mmol) is added.The mixture is heated at 80° C. overnight then concentrated underreduced pressure. The residue was then partitioned between DCM andwater. The aqueous layer was extracted with DCM (×3). The combinedorganic extracts were filtered over phase separator and thenconcentrated under reduced pressure to give the desired crude amide.

General Procedure M

A solution of sulfuric acid (10 eq.) and trifluoroacetic acid (40 eq.)was added to the nitrile derivative (1 eq) and the reaction mixture washeated to 55° C. for 5 h. Once cooled, the mixture was poured into anice-water mixture, carefully neutralized with sodium bicarbonate andthen extracted with EtOAc (×3). The combined organic extracts werewashed with brine, dried over sodium sulfate and concentrated underreduced pressure. Further purification by flash column chromatography onsilica gel gave the desired amide.

General Procedure N

Cesium Carbonate (1.5 eq) was added to a mixture of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(1 eq.) and halide derivative (1.2 eq) in DMF (0.1 M). The reactionmixture was heated to 80° C. for 1.5 h, and then concentrated underreduced pressure. Further purification by either flash columnchromatography on silica gel or by mass-directed semi-preparative HPLCafforded the desired product.

General Procedure O

To a solution of hydrazone (1 eq.) in THF (0.5 M) under a nitrogenatmosphere was added a borane tetrahydrofuran complex solution (BH₃-THF,1.0 M in THF, 2 eq.) at 0° C. The reaction mixture was allowed to returnto RT, stirred for 14 h., and then quenched with methanol (1 mL) andwater. The aqueous layer was extracted with DCM (×3). The combinedorganic extracts were filtered over a hydrophobic frit and concentratedunder reduced pressure. Hydrogen chloride in dioxane (4 M, 10 eq.) wasadded to the residue and the mixture was stirred for 14 h at RT. Themixture was then concentrated under reduced pressure and the residuetaken up with ethanol (0.2 M).2-[(4-Bromophenyl)-methoxy-methylene]propanedinitrile (0.5-1.0 eq.) andTEA (5 eq.) were added and the reaction was then stirred at RT for 14 h.Volatiles were removed under reduced pressure. Water and DCM were addedto the residue and the layers were partitioned. The aqueous layer wasextracted with DCM (×2). The combined organic extracts were filteredover a hydrophobic frit and concentrated under reduced pressure. Furtherpurification by flash column chromatography on silica gel afforded thedesired product.

General Procedure P

1 M borane THF complex (5.0 eq.) was added dropwise under nitrogen to astirred solution of nitrile derivative (1.0 eq.) in anhydrous THF (0.10M). The reaction mixture was then heated at reflux for 4 h before beingcooled to RT. Methanol was added carefully dropwise until evolution ofgas ceased. The solvent was removed under reduced pressure and theresidue was dissolved in methanol and treated with concentrated aqueousHCl. The resulting mixture was heated at reflux for 10 min and thencooled to RT. The solvent was removed under reduced pressure and theresidue was treated cautiously with excess aqueous sodium bicarbonatesolution. The resultant suspension was extracted with ethyl acetate andthe organic layer was dried, filtered and evaporated under reducedpressure to yield the corresponding amine.

General Procedure Q

A solution of acid (1.1 eq.) and 1-hydroxybenzotriazole hydrate (1.1eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(1.1 eq.) in DMF (0.5 M) was stirred at RT for 30 min and then treatedwith the corresponding amine (1.0 eq.), followed by triethylamine (5.0eq.). The reaction mixture was then stirred at RT for 18 h, poured intobrine and extracted with ethyl acetate. The organic layer was washedwith 0.2 M aqueous HCl and brine. The organic layer was then dried,filtered and the solvent evaporated under reduced pressure to yield thedesired crude amide.

General Procedure R

To a nitrogen degassed solution of potassium acetate (3.0 eq),bis(pinacolato)diboron (1.5 eq) and halide derivative (1.0 eq) in1,4-dioxane (0.12 M) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq). The reaction mixture was thendegassed with nitrogen for a further 5 min and then the reaction mixturewas allowed to stir at 90° C. until completion of the reaction. Oncecooled, the mixture was filtered through Celite®. Water was added to thefiltrate and the mixture was partitioned. The aqueous layer wasextracted with ethyl acetate (×3). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and all volatileswere removed under reduced pressure. The resulting residue was eitherused crude or further purified by flash column chromatography on silicagel to afford the desired pinacol ester.

General Procedure S

To a solution of benzhydrazide (1 eq) in toluene (0.5 M) was addedketone (1.5 eq). The reaction mixture was heated to 110° C. for 10-18 h,then cooled to RT. The reaction mixture was poured into water and thenfiltered. The solid was washed with water and further dried to give thedesired crude hydrazone.

General Procedure T

To a solution of hydrazone (1 eq.) in THF (0.2-0.4 M), cooled at 0° C.,was added borane -THF (1 M, 2 eq.). The reaction was allowed to returnto RT and stirred for 3-14 h. The mixture was then cooled to 0° C.,quenched with MeOH and allowed to return to RT. The mixture was thenconcentrated under reduced pressure and the residue was eithertriturated with a suitable solvent (Pet.Ether, Et₂O or EtOAc) to affordthe desired hydrazine or purified by flash column chromatography onsilica gel.

General Procedure U

To a solution of benzohydrazide (1 eq.) in MeOH (0.7 M) was addedhydrogen chloride 37% in water (16 eq). The mixture was heated at 80° C.for 16 h, cooled to RT and concentrated under reduced pressure. EtOAcwas added and the precipitate was filtered and washed twice with EtOActo provide the crude hydrazine salt.

General Procedure W

To a solution of malononitrile (1 eq.) in toluene (0.5 M) and THF (0.5M) was added the corresponding benzoyl chloride (1 eq.). The reactionmixture was cooled down to −10° C. and then N,N-diisopropylethylamine (2eq.) was added dropwise whilst maintaining internal temperature below−10° C. Once addition was complete, the reaction mixture was stirred atRT for 14 h, diluted with EtOAc. The layers were partitioned. Theorganic layer was washed with 1 M HCl then brine, dried with sodiumsulfate, filtered and concentrated under reduced pressure to afford thedesired compound.

General Procedure X

To a solution of dinitrile (1 eq.) in 1,4-dioxane (0.5 M) was addedsodium carbonate (2 eq.) at RT. The reaction was stirred for 10 min thendimethyl sulfate (1.25 eq.) was added dropwise. Once addition wascomplete, the reaction was heated to reflux for 14 h, cooled andconcentrated under reduced pressure. Water was added to the cruderesidue and the mixture was extracted with EtOAc. The combined organicswere dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by flash column chromatographyto afford the desired compound.

General Procedure Y

Allyltrimethylsilane (1.5 eq.) and boron trifluoride diethyl etherate(1.5 eq.) was added to a stirring solution of alkene (1.0 eq.) in DCE(0.5 M). The resulting solution was heated to a reflux for 5 min. Thesolvent was then removed under reduced pressure, and the mixture wastaken up with DMF (0.5 M). Trimethyl(trifluoromethyl)silane (2.0 eq.)and sodium acetate (4.0 eq.) were then added successively. The reactionmixture was left to stir at RT for 2 h, quenched with a saturatedsolution of Na₂CO₃ and diluted with water. The aqueous solution was thenextracted with diethyl ether (×2), dried over a hydrophobic frit, andconcentrated under reduced pressure to afford the desired derivative.

[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 2-methoxybenzoic acid (13.32 mL, 89.45mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (15.24 g,81.32 mmol) afforded the titled compound (20.70 g, 72.61 mmol, 89%yield) as an off-white solid.

UPLC-MS (ES⁺, short acidic): 1.31 min, m/z 286.1 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure C, a mixture of5-amino-3-bromo-1H-pyrazole-4-carbonitrile (6.04 g, 32.32 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (12.90 g, 45.25mmol) gave, after purification by flash column chromatography eluting0-10% with MeOH in DCM,N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(6.45 g, 18.57 mmol, 57% yield) as a light brown solid.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 348.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroacetyl)pyrazole-4-carboxamide

To a degassed solution ofN-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(6.25 g, 17.99 mmol) was added a solution of sulfuric acid (9.59 mL,179.92 mmol) and trifluoroacetic acid (55.3 mL, 719.68 mmol). Thereaction mixture was heated to 55° C. for 5 h. The reaction mixture waspoured into an ice-water mixture, carefully neutralized with sodiumbicarbonate and then extracted with EtOAc (×3). The combined organicextracts were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel eluting 0-10% MeOH in DCM gave5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(5.00 g, 13.68 mmol, 76% yield) as a light brow solid and5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroacetyl)pyrazole-4-carboxamide(0.37 g, 0.80 mmol, 4% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.26 min, m/z 366.2 [M+H]⁺

UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 462.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.31 min, m/z 462.2 [M+H]⁺

Potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide

Potassium bis(trimethylsilyl)amide in toluene (0.5 M, 23.8 mL, 11.9mmol) was added dropwise to a solution of2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 11.3mmol) in dry THF (25 mL) at −78° C. under nitrogen. After stirring for25 mins at −78° C., the mixture was allowed to warm to RT and anhydrousmethanol (1.3 mL, 32.1 mmol) was added. 2-Methoxybenzoyl chloride (3.4mL, 22.6 mmol) was slowly added after 1 h and the mixture was stirredovernight. The resulting suspension was filtered and the filtrateconcentrated under vacuum. The obtained residue was diluted in methanol(25 mL) followed by addition of an aqueous saturated solution ofpotassium hydrogen fluoride (3.5 g, 45.3 mmol). After stirringovernight, the mixture was concentrated under reduced pressure. Theresulting residue was washed with hot acetone (×4). The acetone phaseswere filtered and the filtrate was concentrated under reduced pressureuntil almost all acetone was gone. By subsequent addition of Et₂O, theproduct precipitated and was collected. Potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.50 g, 5.53 mmol,49% yield) was obtained as white solid.

UPLC-MS (ES+, Short acidic): 1.03 min, m/z 232.1 [M−K]⁺

2-[(4-Bromophenyl)-hydroxy-methylene]propanedinitrile

To a solution of 4-bromobenzoyl chloride (7.00 g, 31.9 mmol) andmalononitrile (2.32 g, 35.1 mmol) in toluene (40 mL) and THF (8.6 mL),cooled to −10° C. under a nitrogen atmosphere, was added dropwise asolution of N,N-diisopropylethylamine (11.11 mL, 63.8 mmol) in toluene(30 mL) while maintaining an internal temperature of −10° C. Once theaddition was completed, the reaction mixture stirred at 0° C. for 1 h,then at RT for 18 h. Hydrochloric acid (1 M) was added and the reactionmixture partitioned with EtOAc. The aqueous layer was extracted withEtOAc. The combined organic layer was washed with HCl (1 M), brine,dried over sodium sulfate, filtered and then concentrated under reducedpressure to give 2-[(4-bromophenyl)-hydroxy-methylene]propanedinitrile(7.72 g, 31.0 mmol, 97% yield) as a light brown solid.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.58 (dt, J=8.7, 2.1 Hz, 2H), 7.52 (dt,J=8.8, 2.1 Hz, 2H).

2-[(4-Bromophenyl)-hydroxy-methylene]propanedinitrile

To a 2 L reactor fitted with a thermometer and under nitrogen was added4-bromobenzoyl chloride (200 g, 911 mmol), toluene (1000 mL) and THF(200 mL) and malononitrile (63 mL, 1003 mmol). The reaction mixture wascooled down to −10° C. and then N,N-diisopropylethylamine (318 mL, 1823mmol) was added dropwise to the reaction mixture maintaining an internaltemperature below −10° C. (with the cooling fluid at −20° C.) over 45min. Once the addition was complete the jacket was adjusted to 0° C. for2 h then 25° C. for 2 h. The reaction mixture transferred to a 7 Lseparating funnel and the reactor washed out with 1 M aqueous HCl (1.5L) and EtOAc (1.5 L) consecutively each being transferred to theseparating funnel. The layers were partitioned and the organic layerwashed with 1 M aqueous HCl (250 mL) then brine (250 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated underreduced pressure down to a slurry. This was then slurried with Pet.Ether (500 mL) and filtered. The solid was washed with cold Pet. Ether(100 mL) to give the product after air-drying crude2-[(4-bromophenyl)-hydroxy-methylene]propanedinitrile (232 g). Thismaterial was slurried with a minimum of cold EtOAc and filtered, washedwith minimal EtOAc and diethyl ether to give2-[(4-bromophenyl)-hydroxy-methylene]propanedinitrile (210 g, 843 mmol,93% yield) as a pale yellow solid.

2-[(4-Bromophenyl)-methoxy-methylene]propanedinitrile

A solution of 2-[(4-bromophenyl)-hydroxy-methylene]propanedinitrile(7.00 g, 28.11 mmol) in THF (17 mL) was added dropwise to a suspensionof sodium hydride (1.24 g, 30.92 mmol) in THF (20 mL), cooled to 0° C.After 30 min stirring at 0° C., dimethyl sulfate (7.98 mL, 84.32 mmol)was added and the reaction mixture heated to 80° C. and stirred for 14h. The mixture was cooled to RT, quenched with a saturated solution ofammonium chloride and extracted with EtOAc. The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.Further purification by flash column chromatography on silica geleluting with 20-80% DCM in heptane afforded2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (3.58 g, 13.61mmol, 48% yield) as a white crystalline solid.

UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 263.4 [M]⁺

2-[(4-Bromophenyl)-methoxy-methylene]propanedinitrile

To a solution of 2-[(4-bromophenyl)-hydroxy-methylene]propanedinitrile(210 g, 843 mmol) in 1,4-dioxane (1500 mL) was added sodium carbonate(179 g, 1686 mmol) at RT. The mixture was stirred for 10 min thendimethyl sulfate (100 mL, 1054 mmol) was added dropwise over 10 min. Thereaction mixture was then heated to reflux for 2 h, cooled andpartitioned between water (1.5 L) and DCM (1.5 L). The aqueous layer wasthen extracted with DCM (1 L) and the combined organic extracts werethen washed with water (500 mL) and brine (500 mL), dried over magnesiumsulfate, filtered then concentrated under reduced pressure to give anorange solid. Further purification by flash column chromatography onsilica gel eluting with 50-100% DCM in Pet. Ether then 25% EtOAc in DCM,gave a pale orange solid, which was then slurried with Pet. Ether (500mL) and filtered to give2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (153 g, 582 mmol,69% yield) as an off-white solid.

5-Fluoro-2-methoxy-benzoyl chloride

Oxalyl chloride (124 mL, 1469 mmol) was added to a stirred suspension of5-fluoro-2-methoxybenzoic acid (125 g, 735 mmol) and DMF (2.7 g, 37mmol) in DCM (1750 mL) at RT. The reaction mixture was then allowed tostir at RT for 16 h, concentrated under reduced pressure to give crude5-fluoro-2-methoxy-benzoyl chloride (138 g, 732 mmol, assumedquantitative yield) as a yellow oil that rapidly crystallised.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z: 1.46 min [M+H]⁺ (methylester adduct)

Potassium trifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide

Potassium bis(trimethylsilyl)amide 0.7 M in toluene (174 mL, 770 mmol)was added dropwise to a solution of2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (170 g, 770mmol) in dry THF (1200 mL) at −78° C. under a nitrogen atmosphere. Afterstirring for 25 min at −78° C., the mixture was stirred for a further 10min at 0° C. then for 30 min at RT. Anhydrous methanol (99 g, 3078 mmol)was added at RT and a precipitate was formed. The mixture was stirredfor an additional hour at RT then the reaction mixture was concentratedunder reduced pressure while keeping the water bath at 30° C. Themixture was co-evaporated with THF (2×250 mL). The residue was taken upwith anhydrous THF (750 mL) and 5-fluoro-2-methoxy-benzoyl chloride (138g, 731 mol) in THF (250 mL) was then slowly added. The reaction mixturewas then stirred at RT for 14 h, and then concentrated under reducedpressure. The resulting residue was taken up with ice-cold MeOH (1000mL), the mixture was then cooled to 0° C. before the addition of asaturated solution of potassium hydrogen fluoride (264 g, 3386 mmol inwater (600 mL). The reaction mixture was warmed to RT and stirred for 15h, then concentrated under reduced pressure. The residue was azeotropedtwice with toluene (3×500 mL) to remove the water. The residue was thenwashed with cold TBME and filtered. The white solid was washed with coldacetone (750 mL) then hot 25% MeOH in acetone (3×2000 mL). The filtrateswere concentrated under reduced pressure. Once most of the solvent wasremoved TBME (500 mL) was added and the resultant white solid filteredoff, washed with cold TBME to give potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (198 g,411 mmol, 53% yield).

¹H NMR (400 MHz, DMSO-d₆, □): 7.80-7.71 (m, 1H), 7.64 (dd, J=9.8, 3.4Hz, 1H), 7.31-7.25 (m, 1H), 7.16 (dd, J=9.2, 4.4 Hz, 1H), 3.88 (s, 3H),2.17-2.09 (m, 2H).

4-Bromo-2,6-difluoro-benzoyl chloride

To a suspension of 4-bromo-2,6-difluorobenzoic acid (2 g, 8.44 mmol) inDCM (30 mL) was added oxalyl chloride (0.80 mL, 9.28 mmol) and DMF (0.1mL, 1.30 mmol) at 0° C. The reaction mixture was stirred at RT for 4 h,cooled down to 0° C. More oxalyl chloride (0.79 mL, 9.28 mmol) was addedand the reaction mixture was stirred at RT for 16 h, and thenconcentrated under reduced pressure to give 4-bromo-2,6-difluoro-benzoylchloride (1.58 g, 6.19 mmol, 73% yield).

UPLC-MS: (ES⁺, Short acidic): 1.74 min, m/z 250.9 [M]⁺ (methyl esteradduct)

2-[(4-Bromo-2,6-difluoro-phenyl)-hydroxy-methylene]propanedinitrile

Following general procedure W, malononitrile (450 mg, 6.80 mmol) and4-bromo-2,6-difluoro-benzoyl chloride (1.58 g, 6.19 mmol) gave2-[(4-bromo-2,6-difluoro-phenyl)-hydroxy-methylene]propanedinitrile (2g, 7.05 mmol, assumed quantitative yield) as a thick yellow oil.

UPLC-MS: (ES⁺, Short acidic): 1.13 min, m/z 286.7 [M+2]⁺

2-[(4-Bromo-2,6-difluoro-phenyl)-methoxy-methylene]propanedinitrile

Following general procedure X,2-[(4-bromo-2,6-difluoro-phenyl)-hydroxy-methylene]propanedinitrile(2.01 g, 7.05 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 20-80% DCM in heptane,2-[(4-bromo-2,6-difluoro-phenyl)-methoxy-methylene]propanedinitrile(1.48 g, 4.95 mmol, 70% yield) as a white solid.

UPLC-MS: (ES⁺, Short acidic): 1.69 min, m/z 300.9 [M+2]⁺

2-[(4-Chloro-3,5-difluoro-phenyl)-hydroxy-methylene]propanedinitrile

Following general procedure W, 4-chloro-3,5-difluorobenzoyl chloride(2.00 g, 9.48 mmol) gave2-[(4-chloro-3,5-difluoro-phenyl)-hydroxy-methylene]propanedinitrile(2.48 g, 10.31 mmol, assumed quantitative yield) as a brown thick oil.

UPLC-MS: (ES⁻, Short acidic): 1.34 min, m/z 238.8 [M−H]⁻

2-[(4-Chloro-3,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile

Following general procedure X,2-[(4-chloro-3,5-difluoro-phenyl)-hydroxy-methylene]propanedinitrile(2.48 g, 10.31 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 20-80% DCM in heptane,2-[(4-chloro-3,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(1.68 g, 6.60 mmol, 64% yield) as a pale yellow solid.

UPLC-MS: (ES⁺, Short acidic): 1.70 min, m/z 254.9 [M+H]⁺

2-[(4-Chloro-2,5-difluoro-phenyl)-hydroxy-methylene]propanedinitrile

Following general procedure W, 4-chloro-2,5-difluorobenzoyl chloride(2.00 g, 9.48 mmol) gave2-[(4-chloro-2,5-difluoro-phenyl)-hydroxy-methylene]propanedinitrile(2.66 g, 11.06 mmol, assumed quantitative yield) as a beige solid.

UPLC-MS: (ES⁻, Short acidic): 1.11 min, m/z 238.8 [M−H]⁻

2-[(4-Chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile

Following general procedure X,2-[(4-chloro-2,5-difluoro-phenyl)-hydroxy-methylene]propanedinitrile(2.66 g, 11.06 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 20-80% DCM in heptane,2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(1.64 g, 6.44 mmol, 58% yield) as a pale yellow oil.

UPLC-MS: (ES⁺, Short acidic): 1.67 min, m/z 254.9 [M+H]⁺

4-Chloro-2,3-difluoro-benzoyl chloride

To a suspension of 4-bromo-2,6-difluorobenzoic acid (2.00 g, 8.44 mmol)in DCM (30 mL) was added oxalyl chloride (0.80 mL, 9.28 mmol) and DMF(0.1 mL, 1.30 mmol) at 0° C. The reaction mixture was stirred at RT for4 h, cooled again to 0° C. More oxalyl chloride (0.80 mL, 9.28 mmol) wasadded and the reaction mixture was stirred at RT for 16 h, and thenconcentrated under reduced pressure to give4-chloro-2,3-difluoro-benzoyl chloride (2.19 g, 10.38 mmol, assumedquantitative yield).

UPLC-MS: (ES⁺, Short acidic): 1.74 min, m/z 206.8 [M]⁺ (methyl esteradduct)

2-[(4-Chloro-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile

Following general procedure W, malononitrile (750 mg, 11.42 mmol) and4-chloro-2,3-difluoro-benzoyl chloride (2.19 g, 10.38 mmol) gave crude2-[(4-chloro-2,3-difluoro-phenyl)-hydroxy-methylene]propanedinitrile(2.61 g, 10.85 mmol, assumed quantitative yield) as a brown solid.Following general procedure X,2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile(1.6 g, 6.40 mmol, 59% yield) was obtained as an off-white solid afterpurification by flash column chromatography on silica gel eluting with20-80% DCM in heptane,

UPLC-MS: (ES⁺, Short acidic): 1.70 min, m/z 254.9 [M+H]⁺

Example 1:5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

General procedure H, reacting2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol) andcyclopentylhydrazine hydrochloride (0.91 mmol) to give titled compound(0.83 mmol). UPLC-MS (ES⁺, Short acidic): 2.17 min, m/z 333.2 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K, reacting5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.45mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.45 mmol) to give titled compound (0.36 mmol) as a yellow solid.UPLC-MS (ES⁺, Short acidic): 1.87 min, m/z 416.2 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M, reactingN-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.36 mmol) to give titled compound (0.23 mmol) as an off-white solid.UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 434.2 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 3.59 min, m/z 434.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.51-7.37 (m, 5H), 7.17-7.13 (m, 1H), 7.03 (td, J=7.5, 1.0Hz, 1H), 6.31 (s, 2H), 4.60 (quint, J=7.3 Hz, 1H), 4.54 (d, J=6.1 Hz,2H), 3.90 (s, 3H), 2.02-1.86 (m, 4H), 1.83-1.72 (m, 2H), 1.65-1.51 (m,2H).

The compound of Example 1 can also be made by the process describedbelow.

5-Amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

A solution of 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(72.2 mmol), cyclopentylhydrazine dihydrochloride (72.2 mmol) andtrimethylamine (288.9 mmol) in EtOH (400 mL) was refluxed for 1.5 h. Thereaction mixture was heated to reflux for 1.5 h, cooled and concentratedunder reduced pressure. Work up and purification produced the titledcompound (51.9 mmol) as a pale yellow solid.

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

Potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (36.2mmol), palladium (II) acetate (1.27 mmol), cesium carbonate (108.7 mmol)and 5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(36.2 mmol) were suspended in THF (250 mL) and water (75 mL). The orangereaction mixture was degassed under vacuum and flushed with nitrogenthree times. 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2.54mmol) was added and the mixture was heated to reflux for 4 h.Filteration through Celite®, work up and concentration gave the titledcompound (32.01 mmol) as a pale orange solid.

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

After heating to 55° C. for 3 h, a solution ofN-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(32.0 mmol), sulfuric acid (320.1 mmol) and trifluoroacetic acid (800.3mmol) was cooled and then carefully added into an ice-cooled solution ofsodium bicarbonate (1921 mmol) in water (750 mL) with vigorous stirring.A mixture of heptane/EtOAc (100 mL, 1:1) was added and the mixture wasfiltered. The solid was suspended in 10% MeOH/DCM (750 mL) and water(100 mL). After work-up and crystalisation from EtOAc and MeOH (200 mL)the titled product was obtained (13.15 mmol) as an off-white solid.

Example 2:5-Amino-1-[(1R*,2R*)-2-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazole-4-carbonitrile

General procedure H, reacting2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) and(1R*,2R*)-2-hydrazinocyclopentanol (0.38 mmol) gave the titled compound(0.38 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.82min, m/z 349.1 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,5-amino-3-(4-bromophenyl)-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazole-4-carbonitrile(0.12 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.13 mmol) gavetitled compound (0.11 mmol) as a white powder. UPLC-MS (ES⁺, Shortacidic): 1.60 min, m/z 432.2 [M+H]⁺

5-Amino-1-[(1R*,2R*)-2-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure L,N-[[4-[5-amino-4-cyano-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.10 mmol) gave titled compound (0.05 mmol, 49% yield) as a whitepowder. UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 450.3 [M+H]⁺. UPLC-MS(ES⁺, Long acidic): 3.16 min, m/z 450.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=5.9 Hz, 1H), 7.76 (dd, J=7.6,1.8 Hz, 1H), 7.52-7.38 (m, 5H), 7.18-7.14 (m, 1H), 7.04 (td, J=7.5, 1.0Hz, 1H), 6.26 (s, 2H), 5.03 (d, J=4.6 Hz, 1H), 4.55 (d, J=6.1 Hz, 2H),4.36-4.24 (m, 2H), 3.90 (s, 3H), 2.11-2.00 (m, 1H), 2.00-1.85 (m, 2H),1.79-1.67 (m, 2H), 1.60-1.48 (m, 1H).

Example 3:5-amino-1-tert-butyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-tert-butyl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol) andtert-butylhydrazine hydrochloride (0.86 mmol) gave, after purificationby flash column chromatography on silica gel eluting with 0-5% MeOH inDCM, titled compound (0.52 mmol) as a pale yellow solid. UPLC-MS (ES⁺,Short acidic): 2.21 min, m/z 321.0 [M+2]⁺

N-[[4-(5-Amino-1-tert-butyl-4-cyano-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-tert-butyl-pyrazole-4-carbonitrile (0.22mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.24 mmol) afforded, after purification by flash column chromatographyon silica gel eluting with 0-10% MeOH in DCM, titled compound (0.21mmol, 98% yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.90min, m/z 404.2 [M+H]⁺

5-Amino-1-tert-butyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure L,N-[[4-(5-amino-1-tert-butyl-4-cyano-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.74 mmol) gave, after purification by flash column chromatography onsilica gel, titled compound (0.03 mmol) as a pale yellow solid. UPLC-MS(ES⁺, Short acidic): 1.61 min, m/z 422.3 [M+H]⁺. UPLC-MS (ES⁺, Longacidic): 3.57 min, m/z 422.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.50-7.37 (m, 5H), 7.17-7.13 (m, 1H), 7.03 (td, J=7.5, 1.1Hz, 1H), 6.28 (s, 2H), 4.54 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 1.56 (s,9H).

Example 4:5-Amino-1-(3-bicyclo[3.1.0]hexanyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Bicyclo[3.1.0]hexan-3-one

To a solution of pyridine (1.68 mmol) and pyridinium chlorochromate(7.64 mmol) in DCM (6 mL), cooled to 0° C., was added dropwisecis-bicyclo[3.1.0]hexan-3-ol (5.09 mmol). The reaction mixture was thenleft to warm to RT and left to stir overnight. The reaction mixture wasdiluted with diethyl ether and the black residue was washed with morediethyl ether (×3). The combined organics were then passed through a padof florisil and the solvent was removed under reduced pressure to affordtitled compound as a crude yellow oil. ¹H NMR (400 MHz, CDCl₃, □):2.64-2.54 (m, 2H), 2.20-2.12 (m, 2H), 1.57-1.50 (m, 2H), 0.94-0.86 (m,1H), −0.03-−0.08 (m, 1H).

tert-Butyl N-(3-bicyclo[3.1.0]hexanylideneamino)carbamate

A mixture of bicyclo[3.1.0]hexan-3-one (5.58 mmol) and tert-butylcarbazate (5.58 mmol) in methanol (20 mL) was stirred at RT for 4 h. Thereaction mixture was then concentrated under reduced pressure. Thereaction mixture was quenched with water (20 mL), extracted with DCM(3×20 mL). The combined organic extracts were filtered over ahydrophobic frit and then concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel, eluting with 0-100% EtOAc in heptane, to give titled compound (2.84mmol) as a clear oil. ¹H NMR (400 MHz, CDCl₃, □): 2.85-2.77 (m, 1H),2.63-2.56 (m, 1H), 2.39-2.35 (m, 2H), 1.52-1.35 (m, 12H), 0.74-0.66 (m,1H), −0.13-−0.18 (m, 1H).

3-Bicyclo[3.1.0]hexanylhydrazine; 2,2,2-trifluoroacetic acid

Sodium cyanoborohydride (4.71 mmol) was added portionwise to a stirredsolution of tert-butyl N-(3-bicyclo[3.1.0]hexanylideneamino)carbamate(4.76 mmol) in acetic acid (7 mL) and water (7 mL). The resultingmixture was left to stir at RT for 2 h, neutralised by addition of 1 MNaOH (aq.), and then extracted with DCM (×2). The combined organicextracts were washed with a saturated solution of sodium bicarbonate,dried over sodium sulfate, filtered and concentrated to dryness, to givecrude tert-butyl N-(3-bicyclo[3.1.0]hexanylamino)carbamate (4.71 mmol)as a clear oil. The crude product was taken up in DCM (4.5 mL).Trifluoroacetic acid (58.77 mmol) was added dropwise a stirred solutionof tert-butyl N-(3-bicyclo[3.1.0]hexanylamino)carbamate (4.71 mmol) inDCM (4.5 mL). The resulting solution was stirred for 2 h and thenconcentrated under reduced pressure to give crude titled compound (4.42mmol) as a clear oil.

¹H NMR (400 MHz, CDCl₃, □): 3.88-3.78 (m, 1H), 2.43-2.31 (m, 2H), 1.74(dd, J=14.9, 4.9 Hz, 2H), 1.40-1.24 (m, 2H), 0.83-0.75 (m, 1H),0.17-0.11 (m, 1H).

5-Amino-1-(3-bicyclo[3.1.0]hexanyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.78 mmol) and3-bicyclo[3.1.0]hexanylhydrazine; 2,2,2-trifluoroacetic acid (1.17 mmol)gave, after purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane, the titled compound (0.21 mmol) asa colourless oil. UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 345.1[M+2]⁺

N-[[4-[5-Amino-1-(3-bicyclo[3.1.0]hexanyl)-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-1-(3-bicyclo[3.1.0]hexanyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile(0.21 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.21 mmol)afforded the titled compound (0.23 mmol). UPLC-MS (ES⁺, Short acidic):1.86 min, m/z 428.2 [M+H]⁺

5-Amino-1-(3-bicyclo[3.1.0]hexanyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-1-(3-bicyclo[3.1.0]hexanyl)-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.21 mmol) afforded the titled compound (0.04 mmol) after purificationby mass-directed semi-preparative HPLC. UPLC-MS (ES⁺, Short acidic):1.68 min, m/z 446.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.72 min, m/z446.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.2 Hz, 1H), 7.77 (dd, J=7.7,1.8 Hz, 1H), 7.54-7.38 (m, 5H), 7.16 (dd, J=8.4, 0.7 Hz, 1H), 7.04 (td,J=7.5, 1.0 Hz, 1H), 6.29 (s, 2H), 5.01-4.83 (m, 1H), 4.55 (d, J=6.1 Hz,2H), 3.91 (s, 3H), 2.46-2.36 (m, 2H), 1.92 (dd, J=13.8, 4.8 Hz, 2H),1.35-1.27 (m, 2H), 0.81 (q, J=4.1 Hz, 1H), 0.66-0.54 (m, 1H).

Example 5:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-methylcyclopentyl)pyrazole-4-carboxamide

tert-Butyl N-[(3-methylcyclopent-2-en-1-ylidene)amino]carbamate

To a solution of 3-methyl-2-cyclopenten-1-one (10.40 mmol) in methanol(59.4 mL) was added tert-butyl carbazate (10.92 mmol) and the reactionwas stirred at RT for 16 h. Volatiles were removed under reducedpressure to give the titled compound (12.18 mmol). ¹H NMR (400 MHz,DMSO-d₆, □): 5.98-5.93 (m, 1H), 3.26-3.05 (br s, 1H), 2.62-2.57 (m, 2H),2.44-2.41 (m, 2H), 2.15 (s, 3H), 1.47 (s, 9H).

(3-Methylcyclopentyl)hydrazine

To a solution of tert-butylN-[−(3-methylcyclopent-2-en-1-ylidene)amino]carbamate (10.40 mmol) inTHF/MeOH (21 mL, 1:1) was added sodium cyanoborohydride (12.50 mmol)portion-wise. The reaction was heated under reflux under a nitrogenatmosphere for 10 min and then cooled to RT. Hydrogen chloride (30.00mmol) was added and the reaction mixture was heated under reflux for 3h, cooled to RT and stirred for 16 h. The reaction was filtered toremove inorganic insoluble material and the filtrate was concentratedunder reduced pressure and azeotroped (×3) with toluene. The residue wasdissolved in hot isopropanol, cooled to RT, diluted with ether and thencooled to 0° C. The precipitate was filtered and the filtrate wasconcentrated under vacuum to give the titled compound (6.50 mmol). ¹HNMR (400 MHz, DMSO-d₆, □ □ □ mixture of diastereoisomers): 3.83-3.62 and3.56-3.38 (m, 1H), 3.10-2.99 and 2.78-2.68 (m, 2H), 2.26-2.01 (m, 2H),2.00-1.57 (m, 5H), 1.40-1.02 (m, 1H), 0.99 and 0.93 (d, 7=6.5 Hz, 3H).

5-Amino-3-(4-bromophenyl)-1-(3-methylcyclopentyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) and(3-methylcyclopentyl)hydrazine (0.38 mmol) afforded the titled compound(0.07 mmol) after purification by flash column chromatography on silicagel eluting with 0-2% MeOH in DCM. UPLC-MS (ES⁺, Short acidic): 2.26min, m/z 345.1 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(3-methylcyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3-methylcyclopentyl)pyrazole-4-carbonitrile(0.08 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.08 mmol)afforded the titled compound (0.05 mmol) after purification by flashcolumn chromatography on silica gel eluting with 0-10% MeOH in DCM.UPLC-MS (ES⁺, Short acidic): 2.03 min, m/z 430.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-methylcyclopentyl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-methylcyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.08 mmol) afforded the titled compound (0.01 mmol) after purificationby purification by mass-directed semi-preparative HPLC. UPLC-MS (ES⁺,Short acidic): 1.73 min, m/z 448.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):3.86 min, m/z 448.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □) (mixture of diasteroisomers): 8.74 (t,J=6.0 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H), 7.53-7.38 (m, 5H), 7.16 (d,J=7.8 Hz, 1H), 7.04 (td, J=7.5, 0.9 Hz, 1H), 6.31 (s, 2H), 4.79-4.58 (m,1H), 4.55 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.30-2.21 (m, 0.5H),2.17-2.05 (m, 1.5H), 2.01-1.92 (m, 2.5H), 1.85-1.75 (m, 0.5H), 1.64-1.51(m, 1H), 1.44-1.33 (m, 0.5H), 1.21-1.11 (m, 0.5H), 1.02 (dd, J=21.0, 6.6Hz, 3H).

Example 6:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (80 mg, 0.30 mmol)and 5-(trifluoromethyl)pyrid-2-ylhydrazine (0.30 mmol) gave the titledcompound (0.30 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic):2.27 min, m/z 408.1 [M]⁺

N-[[4-[5-Amino-4-cyano-1-[5-(trifluoromethyl)-2-pyridyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-carbonitrile(0.10 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.12 mmol) gavetitled compound (0.06 mmol) as white powder. UPLC-MS (ES⁺, Shortacidic): 2.03 min, m/z 493.3 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-[5-(trifluoromethyl)-2-pyridyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.06 mmol) gave the titled compound (0.03 mmol) as a white powder.UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 511.3 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 4.19 min, m/z 511.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □):8.90-8.86 (m, 1H), 8.79 (t, J=6.1 Hz, 1H), 8.38 (dd, J=8.9, 2.3 Hz, 1H),8.05 (d, J=8.8 Hz, 1H), 7.83-7.74 (m, 3H), 7.60 (d, J=8.1 Hz, 2H),7.53-7.45 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.09-7.02 (m, 1H), 4.59 (d,J=6.0 Hz, 2H), 3.92 (s, 3H).

Example 7:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(methoxymethoxy)ethyl]pyrazole-4-carboxamide

General procedure N, a mixture of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.26 mmol) and 1-bromo-2-(methoxymethoxy)ethane (0.39 mmol) afforded,after purification by mass-directed semi-preparative HPLC (middlemethod), the titled compound (0.03 mmol). UPLC-MS (ES⁺, Short acidic):1.42 min, m/z 454.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z454.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.1 Hz, 1H), 7.75(dd, J=7.7, 1.8 Hz, 1H), 7.51-7.38 (m, 5H), 7.18-7.13 (m, 1H), 7.04 (td,J=7.5, 1.0 Hz, 1H), 6.30 (s, 2H), 4.57-4.52 (m, 4H), 4.10 (t, J=5.7 Hz,2H), 3.90 (s, 3H), 3.77 (t, J=5.7 Hz, 2H), 3.19 (s, 3H).

Example 8:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-carboxamide

General procedure N, a mixture of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.25 mmol) and 3-(chloromethyl)-3-methyloxetane (0.38 mmol) gave, afterpurification by mass-directed semi-preparative HPLC, the titled compound(0.07 mmol). UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 450.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.11 min, m/z 450.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7, 1.8 Hz, 1H),7.51-7.38 (m, 5H), 7.17-7.13 (m, 1H), 7.04 (td, J=7.5, 1.5 Hz, 1H), 6.41(s, 2H), 4.63 (d, J=5.9 Hz, 2H), 4.54 (d, J=6.1 Hz, 2H), 4.20 (d, J=5.9Hz, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 1.24 (s, 3H).

Example 9:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-morpholinoethyl)pyrazole-4-carboxamide

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-morpholinoethyl)pyrazole-4-carboxamide

General procedure N,5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.27 mmol) and JV-chloroethylmorpholine hydrochloride (0.41 mmol)afforded the titled compound (0.04 mmol) after purification by flashcolumn chromatography on silica gel eluting with 0-5% MeOH in DCM.UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 479.3 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 2.51 min, m/z 479.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □):8.74 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.53-7.37 (m, 5H),7.16 (d, J=8.2 Hz, 1H), 7.05 (td, J=7.5, 1.0 Hz, 1H), 6.40 (s, 2H), 4.55(d, J=6.1 Hz, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.90 (s, 3H), 3.60-3.56 (m,4H), 2.69-2.65 (m, 2H), 2.47-2.44 (m, 4H).

Example 10:5-Amino-1-(3,3-dimethyl-2-oxo-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(3,3-dimethyl-2-oxo-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure N,5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.24 mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.36 mmol) afforded thetitled compound (0.03 mmol) after purification by flash columnchromatography on silica gel eluting with 0-5% MeOH in DCM. UPLC-MS(ES⁺, Short acidic): 1.55 min, m/z 464.3 [M+H]⁺. UPLC-MS (ES⁺, Longacidic): 3.49 min, m/z 464.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.74(t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H), 7.53-7.37 (m, 5H), 7.17(d, J=8.2 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz, 1H), 6.27 (s, 2H), 5.12 (s,2H), 4.55 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 1.18 (s, 9H).

Example 11:5-Amino-1-(2-cyanoethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(2-cyanoethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure N,5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.25 mmol) and 3-bromopropionitrile (0.37 mmol) afforded the titledcompound (0.07 mmol) after purification by flash column chromatographyon silica gel eluting with 0-5% MeOH in DCM.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 419.2 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 3.02 min, m/z 419.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □):8.75 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H), 7.53-7.37 (m, 5H),7.16 (d, J=7.7 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz, 1H), 6.49 (s, 2H), 4.56(d, J=6.1 Hz, 2H), 4.22 (t, J=6.7 Hz, 2H), 3.90 (s, 3H), 2.97 (t, J=6.7Hz, 2H).

Example 12:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclohexyl)pyrazole-4-carboxamide

A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 mmol) in MeCN(0.5 mL) was slowly added to a solution of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.27 mmol) in MeCN (2 mL). The reaction was stirred at RT for 15 minbefore cyclohex-2-enone (0.55 mmol) was added. The reaction mixture wasstirred for 16 h. Water was added and the reaction mixture extractedwith EtOAc. The combined organic layer was dried over sodium sulfate andevaporated in vacuo. Purification by flash column chromatography onsilica gel eluting with 0-5% MeOH in DCM gave the titled compound (0.15mmol) as a pale brown solid. UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z462.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.00 min, m/z 462.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.73 (t, J=6.2 Hz, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.51-7.45 (m, 3H), 7.42-7.37 (m, 2H), 7.17-7.13 (m, 1H),7.04 (td, J=7.6, 1.0 Hz, 1H), 6.38 (d, J=1.8 Hz, 1H), 6.09 (s, 1H), 4.54(d, J=6.2 Hz, 2H), 4.53-4.49 (m, 1H), 3.89 (s, 3H), 2.13-2.05 (m, 1H),2.01-1.95 (m, 1H), 1.89-1.79 (m, 2H), 1.78-1.68 (m, 1H), 1.67-1.54 (m,2H) 1.29-1.06 (m, 1H).

Example 13:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole-4-carboxamide

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole-4-carboxamide

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.14 mmol) was added to a mixture of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.27 mmol) and 2-cyclopentenone (0.33 mmol) in MeCN (0.54 mL). Thereaction mixture was stirred at RT for 2 days and ten concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with 0-3.5% MeOH in DCM, followedby reverse-phase chromatography eluting with 20-40% MeCN in watercontaining 0.1% formic acid additive, to give the titled compound (0.04mmol, 14% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 448.2 [M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 3.09 min, m/z 448.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.76-8.69 (m, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J=8.2 Hz, 1H), 7.07-7.00 (m, 1H),6.42 (s, 2H), 5.05-4.95 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.90 (s, 3H),2.73-2.61 (m, 1H), 2.60-2.30 (m, 3H), 2.27-2.11 (m, 2H).

Example 14:5-Amino-1-(2-hydroxy-3,3-dimethyl-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(2-hydroxy-3,3-dimethyl-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-amino-1-(3,3-dimethyl-2-oxo-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamidesolution (0.07 mmol) in MeOH (1 mL) was added dropwise to sodiumborohydride (0.07 mmol) solution in MeOH (1 mL) at 0° C. The reactionmixture was stirred for 30 min then diluted with DCM. A saturated aq.Na₂CO₃ solution was then added and the mixture was extracted with DCM(×3). The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel eluting with 0-5% MeOH in DCMto give the titled compound (0.03 mmol). UPLC-MS (ES⁺, Short acidic):1.62 min, m/z 466.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.49 min, m/z466.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.1 Hz, 1H), 7.76(dd, J=7.7, 1.8 Hz, 1H), 7.38-7.54 (m, 5H), 7.16 (d, J=8.1 Hz, 1H), 7.05(td, J=7.5, 0.9 Hz, 1H), 6.10 (s, 2H), 5.10 (d, J=5.9 Hz, 1H), 4.56 (d,J=6.1 Hz, 2H), 3.99 (dd, J=14.3, 1.7 Hz, 1H), 3.91 (s, 3H), 3.78 (dd,J=14.2, 9.5 Hz, 1H), 3.47-3.59 (m, 1H), 0.92 (s, 9H).

Example 15:5-Amino-1-(2,4-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2,4-difluorophenyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.30 mmol) and2,4-difluorophenylhydrazine hydrochloride (0.30 mmol) gave the titledcompound (0.22 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic):1.99 min, m/z 375.1 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,4-difluorophenyl)pyrazole-4-carbonitrile(0.11 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.19 mmol) gavethe titled compound (0.10 mmol) as a white powder. UPLC-MS (ES⁺, Shortacidic): 1.73 min, m/z 460.2 [M+H]⁺

5-Amino-1-(2,4-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.10 mmol) gave the titled compound (0.05 mmol) as an off-white powder.

UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 478.2 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 3.58 min, m/z 478.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □):8.76 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H), 7.69-7.60 (m, 1H),7.60-7.40 (m, 6H), 7.32-7.23 (m, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.08-7.01(m, 1H), 6.46 (s, 2H), 4.57 (d, J=6.1 Hz, 2H), 3.90 (s, 3H).

Example 16:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) and[3-(trifluoromethyl)phenyl]hydrazine hydrochloride (0.38 mmol) gave thetitled compound (0.31 mmol) as an off-white solid. UPLC-MS (ES⁺, Shortacidic): 2.18 min, m/z 407.1 [M]⁺

5-Amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide

General procedure nitrile hydrolysis,5-amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carbonitrile(0.12 mmol) gave the titled compound crude (0.12 mmol) as a clear oil.UPLC-MS (ES⁺, Short acidic): 1.93 min, m/z 425.0 [M]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide(0.12 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.18 mmol) gavethe titled compound (0.08 mmol) as an off-white powder. UPLC-MS (ES⁺,Short acidic): 1.79 min, m/z 510.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):4.06 min, m/z 510.6 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.77 (t, J=6.1Hz, 1H), 8.02-7.92 (m, 2H), 7.83-7.73 (m, 3H), 7.57 (d, J=8.1 Hz, 2H),7.53-7.43 (m, 3H), 7.16 (d, J=7.2 Hz, 1H), 7.08-7.02 (m, 1H), 6.65 (s,2H), 4.58 (d, J=6.1 Hz, 2H), 3.91 (s, 3H)

Example 17:5-amino-1-(cyclohexylmethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure N, a mixture of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.26 mmol) and (bromomethyl)cyclohexane (0.39 mmol) afforded, afterpurification by mass-directed semi-preparative HPLC, titled compound(0.04 mmol).

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 462.3 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 3.88 min, m/z 462.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □):8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.51-7.38 (m, 5H),7.18-7.14 (m, 1H), 7.04 (td, J=7.5, 1.0 Hz, 1H), 6.31 (s, 2H), 4.55 (d,J=6.1 Hz, 2H), 3.90 (s, 3H), 3.75 (d, J=7.2 Hz, 2H), 1.88-1.75 (m, 1H),1.73-1.53 (m, 5H), 1.27-1.09 (m, 3H), 1.06-0.91 (m, 2H).

Example 18:5-amino-1-cyclohexyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-cyclohexyl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol) andcyclohexylhydrazinehydrochloride (0.91 mmol) gave, after purification byflash column chromatography on silica gel eluting with 0-5% MeOH in DCM,the titled compound (0.65 mmol) as a white solid. UPLC-MS (ES⁺, Shortacidic): 2.11 min, m/z 347.1 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-cyclohexyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-cyclohexyl-pyrazole-4-carbonitrile (0.64mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.70 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-5% MeOH in DCM, the titled compound (0.59mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.81 min, m/z 430.3[M+H]⁺

5-Amino-1-cyclohexyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclohexyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.58 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-5% MeOH in DCM, the titled compound (0.32mmol) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 448.3 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 3.63 min, m/z 448.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6,1.7 Hz, 1H), 7.52-7.38 (m, 5H), 7.19-7.14 (m, 1H), 7.04 (td, J=7.6, 0.9Hz, 1H), 6.32 (s, 2H), 4.55 (d, J=6.1 Hz, 2H), 4.12-4.03 (m, 1H), 3.90(s, 3H), 1.76-1.60 (m, 8H), 1.45-1.29 (m, 2H).

Example 19:5-amino-1-isopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-isopropyl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) andisopropylhydrazine (0.46 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-2% MeOH in DCM, the titledcompound (0.27 mmol) as a pale yellow solid. UPLC-MS (ES⁺, Shortacidic): 1.96 min, m/z 307.1 [M+2]⁺

N-[[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-isopropyl-pyrazole-4-carbonitrile (0.27mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.27 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.19mmol) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z390.2 [M+H]⁺

5-Amino-1-isopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.19 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-5% MeOH in DCM, the titled compound (0.10mmol) as a off-white solid. UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z408.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 408.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.50-7.38 (m, 5H), 7.18-7.13 (m, 1H), 7.04 (td, J=7.5, 0.9Hz, 1H), 6.31 (s, 2H), 4.54 (d, J=6.1 Hz, 2H), 4.47 (quint, J=6.6 Hz,1H), 3.90 (s, 3H), 1.33 (d, J=6.6 Hz, 6H).

Example 20:5-Amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Sodium borohydride (0.20 mmol) was added to a solution of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole-4-carboxamide(0.18 mmol) in methanol (1 mL), cooled to 0° C. The reaction mixture wasthen stirred at rt for 30 min, quenched with a saturated solution ofammonium chloride and partitioned. The aqueous layer was extracted withDCM (×3). The combined organic extracts were filtered over a hydrophobicfrit, and concentrated under reduced pressure. Further purification byreverse-phase chromatography eluting with 20-40% MeCN in watercontaining 0.1% formic acid additive afforded the titled compound (0.08mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z450.3 [M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 3.04 min, m/z 450.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.5, 1.8 Hz, 1H),7.55-7.38 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.07-7.01 (m, 1H), 6.40 (s,2H), 5.07 (d, J=5.7 Hz, 1H), 4.65 (quint, J=7.7 Hz, 1H), 4.55 (d, J=6.1Hz, 2H), 4.18-4.09 (m, 1H), 3.91 (s, 3H), 2.32-2.21 (m, 1H), 2.08-1.92(m, 2H), 1.92-1.83 (m, 1H), 1.82-1.62 (m, 2H)

Example 21:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) and2,2,2-trifluoroethyl hydrazine (70% wt in water, 0.46 mmol) gave, afterfurther purification by flash column chromatography on silica geleluting with 0-10% MeOH in DCM, the titled compound (0.27 mmol) as alight yellow solid. LC-MS (ES⁺, Method 1): 5.80 min, m/z 345.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(0.29 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.38 mmol) gave,after further purification by flash column chromatography on silica geleluting with 10-100% EtOAc in heptane, the titled compound (0.17 mmol)as an off-white solid. LC-MS (ES⁺, Method 1): 5.01 min, m/z 430.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.16 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 10-100% EtOAc in heptane, thetitled compound (0.08 mmol) as a white solid. UPLC-MS (ES+, Shortacidic): 1.54 min, m/z 448.2 [M+H]⁺. UPLC-MS (ES+, Long acidic): 3.22min, m/z 448.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.75 (t, J=6.0 Hz,1H), 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.40 (m, 5H), 7.16 (d, J=8.1 Hz,1H), 7.07-7.02 (m, 1H), 6.68 (s, 2H), 4.95 (q, J=9.0 Hz, 2H), 4.56 (d,J=6.1 Hz, 2H), 3.91 (s, 3H)

Example 22:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-phenyl-pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.35 mmol) andphenylhydrazine (0.42 mmol) gave, after further purification by flashcolumn chromatography on silica gel eluting with 0-10% MeOH in DCM,5-amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carbonitrile (0.28 mmol)as a white solid.

UPLC-MS (ES+, Short acidic): 2.04 min, m/z 339.1 [M]⁺

N-[[4-(5-amino-4-cyano-1-phenyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carbonitrile (0.12 mmol)and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.19mmol) gave, after further purification by flash column chromatography onsilica gel eluting with 10-100% EtOAc in heptane, the titled compound(0.09 mmol) as an off-white solid.

UPLC-MS (ES+, Short acidic): 1.77 min, m/z 424.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-phenyl-pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-phenyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.07 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.05 mmol) as a white solid. LC-MS (ES+, Method 1): 4.53 min,m/z 442.2 [M+H]⁺. UPLC-MS (ES+, Long acidic): 3.39 min, m/z 442.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6,2.0 Hz, 1H), 7.65-7.60 (m, 2H), 7.59-7.38 (m, 8H), 7.16 (d, J=8.1 Hz,1H), 7.08-7.02 (m, 1H), 6.49 (s, 2H), 4.58 (d, J=6.1 Hz, 2H), 3.91 (s,3H).

Example 23:5-Amino-1-[(1R)-indan-1-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-[(1R)-indan-1-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

A suspension ofN-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(100 mg, 0.29 mmol), (S)-(+)-1-indanol (0.49 mmol) andtriphenylphosphine (0.49 mmol) in anhydrous THF (2 mL) was cooled to 0°C. Diisopropyl azodicarboxylate (0.49 mmol) was added dropwise over 5min and the reaction mixture was allowed to return to RT over 30 min andthen stirred for 16 h. The reaction mixture was concentrated undervacuum. Further purification by SPE SCX column eluting with MeOH gavethe titled compound (0.17 mmol). UPLC-MS (ES⁺, Short acidic): 1.90 min,m/z 464.3 [M+H]⁺

5-Amino-1-[(1R)-indan-1-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-[(1R)-indan-1-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.27 mmol) afforded the titled compound (0.03 mmol) after purificationby flash column chromatography on silica gel eluting with 0-5% MeOH inDCM. UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 482.3 [M+H]⁺. UPLC-MS(ES⁺, Long acidic): 3.77 min, m/z 482.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.70 (t, J=6.1 Hz, 1H), 7.74 (dd, J=7.6,1.7 Hz, 1H), 7.52-7.43 (m, 1H), 7.41-7.34 (m, 4H), 7.30 (d, J=7.4 Hz,1H), 7.24 (t, J=7.1 Hz, 1H), 7.20-7.11 (m, 2H), 7.09-6.98 (m, 2H), 6.56(s, 2H), 5.91 (t, J=7.5 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.88 (s, 3H),3.21-3.06 (m, 1H), 2.97-2.84 (m, 1H), 2.49-2.38 (m, 2H).

Example 24:1-Cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxamide

Methyl 2-(4-bromobenzoyl)-3-oxo-butanoate

Under N₂, a methylmagnesium bromide solution (2.2 M in THF, 9.27 mmol)was added to a solution of methyl acetoacetate (9.27 mmol) in THF (44mL) at 0° C. and then allowed to stir at 0° C. for 30 min. Then4-bromobenzoyl chloride (9.27 mmol) was added and then allowed to stirat RT for 16 h. Afterwards, quenched with a saturated solution ofammonium chloride. Then the aqueous layer was extracted with DCM (×3),organics combined, filtered over a hydrophobic frit and all volatileswere removed under reduced pressure. Purification by flash columnchromatography on silica gel eluting with 0-15% EtOAc in heptaneafforded the titled compound (4.99 mmol) as a clear oil. UPLC-MS (ES⁺,Short acidic): 1.88 min, m/z 299.0 [M]⁺

Methyl 3-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylate

A hydrazine hydrate solution (55-60% in water, 3.99 mmol) was added to asolution of methyl 2-(4-bromobenzoyl)-3-oxo-butanoate (4.99 mmol) inacetic acid (20 mL). Afterwards, allowed to stir at RT for 72 h and thenall volatiles were removed under reduced pressure. Afterwards, theresidue was basified with a saturated solution of sodium carbonate. Thenthe aqueous layer was extracted with DCM (×3), extracts combined andfiltered over a hydrophobic frit. Afterwards, purification by flashcolumn chromatography on silica gel eluting with 0-6% MeOH in DCMafforded the titled compound (4.21 mmol) as a clear oil. UPLC-MS (ES⁺,Short acidic): 1.60 min, m/z 296.9 [M+2]⁺

Methyl 3-(4-bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylate

Cesium carbonate (3.00 mmol) was added to a solution ofbromocyclopentane (2.40 mmol) and methyl3-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylate (1.20 mmol) in DMF(2.5 mL). Afterwards, allowed to stir at 75° C. for 45 min and then allvolatiles were removed under reduced pressure. Then the residue wassuspended in EtOAc (50 mL). Afterwards, the organic layer was washedwith water (×2) and a saturated solution of brine (×1). Then the organiclayer was dried over sodium sulphate, filtered and all volatiles wereremoved under reduced pressure. Purification by flash columnchromatography on silica gel eluting with 0-40% EtOAc in heptaneafforded the titled compound (0.87 mmol) as a clear oil. UPLC-MS (ES⁺,Short acidic): 2.27 min, m/z 365.1 [M+2]⁺

3-(4-Bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid

Lithium hydroxide (2.75 mmol) was added to a solution of methyl3-(4-bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylate (0.28mmol) in 1,4-dioxane (0.75 mL) and water (0.75 mL). Afterwards, allowedto stir at 80° C. for 16 h followed by at 100° C. for 16 h. Afterallowing the reaction mixture to cool back down to RT, the reactionmixture was acidified to pH3 with hydrochloric acid (1M). Then extractedwith DCM (×3), filtered over a hydrophobic frit and all volatiles wereremoved under reduced pressure. Purification by flash columnchromatography on silica gel eluting with 0-20% EtOAc in heptaneafforded titled compound (0.28 mmol) as a white solid. UPLC-MS (ES⁺,Short acidic): 2.00 min, m/z 351.1 [M+2]⁺

3-(4-Bromophenyl)-1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazole-4-carboxamide

Under N₂, 3-(4-bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylicacid (0.28 mmol), 2,4-dimethoxybenzylamine (0.33 mmol) and triethylamine(0.41 mmol) were suspended in THF (1.4 mL). After allowing the reactionmixture to stir at RT for 5 min, a solution of propylphosphonicanhydride (50 wt % in EtOAc, 0.41 mmol) was added and the reaction wasstirred at RT for 72 h. Then 2,4-dimethoxybenzylamine (0.33 mmol),triethylamine (0.41 mmol) and a solution of propylphosphonic anhydride(50 wt % in EtOAc, 0.41 mmol) were added. Then the reaction was allowedto stir at RT for 16 h. Then a saturated solution of ammonium chloride(10 mL) and water (10 mL) were added. Afterwards, DCM (×3) was used toextract the aqueous layer. The organic extracts were combined, filteredover a hydrophobic frit, and all volatiles were removed under reducedpressure. Purification by flash column chromatography on silica geleluting with 0-50% EtOAc in heptane followed by purification byreverse-phase chromatography eluting with 30-70% MeCN in watercontaining 0.1% formic acid afforded the titled compound (0.07 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 2.18 min, m/z 500.2 [M+2]⁺

1-Cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxamide

Following general procedure K,3-(4-bromophenyl)-1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazole-4-carboxamide(0.07 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.11 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 0-2.5% MeOH in DCM followed by reverse-phase chromatography elutingwith 20-70% MeCN in water containing 0.1% formic acid, the titledcompound (0.05 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 2.04min, m/z 583.4 [M+H]⁺

1-Cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxamide

At 0° C., trifluoroacetic acid (0.04 mmol) was added to a solution of1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxamide(0.04 mmol) in DCM (0.4 mL) and the reaction mixture was stirred for 48h at rt. Extra portions of trifluoroacetic acid (0.04 mmol) were thenadded every 24 h for 3 days whilst allowing the reaction mixture to stirat rt. The reaction mixture was then basified with a saturated solutionof sodium carbonate. The layers were partitioned and the aqueous layerwas extracted with DCM (×3), combined, filtered over a hydrophobic fritand concentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel eluting with 0-6% MeOH in DCM,followed by reverse-phase chromatography eluting with 20-70% MeCN inwater containing 0.1% formic acid additive, afforded the titled compound(0.02 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.62min, m/z 433.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.70 min, m/z 433.2[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.70 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.6,1.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.51-7.45 (m, 1H), 7.34 (d, J=8.2Hz, 2H), 7.24-7.17 (m, 2H), 7.16 (d, J=8.3 Hz, 1H), 7.08-7.01 (m, 1H),4.71 (quint, J=7.3 Hz, 1H), 4.51 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 2.37(s, 3H), 2.11-1.91 (m, 4H), 1.91-1.80 (m, 2H), 1.71-1.55 (m, 2H)

Example 25:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(1H-tetrazol-5-yl)ethyl]pyrazole-4-carboxamide

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(1H-tetrazol-5-yl)ethyl]pyrazole-4-carboxamide

To a solution of5-amino-1-(2-cyanoethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(0.27 mmol) in DMF (2 mL) was added sodium azide (0.28 mmol) andammonium chloride (0.30 mmol). The reaction mixture was heated to 110°C. for 16 h. A further sodium azide (0.28 mmol) and ammonium chloride(0.30 mmol) were added and the mixture was heated to 110° C. for 16 h,cooled to RT and concentrated under vacuum. The resulting residue waspurified by flash column chromatography on silica gel, eluting with0-20% MeOH in DCM, to give the titled compound (0.02 mmol). UPLC-MS(ES⁺, Short acidic): 1.22 min, m/z 462.2 [M+H]⁺. UPLC-MS (ES⁺, Longacidic): 2.70 min, m/z 462.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.1 Hz, 1H), 8.32 (br s, 1H),7.76 (dd, J=7.6, 1.9 Hz, 1H), 7.45-7.52 (m, 1H), 7.44-7.38 (m, 4H), 7.16(d, J=7.7 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz, 1H), 6.48 (s, 2H), 4.55 (d,J=6.2 Hz, 2H), 4.33 (t, J=7.1 Hz, 2H), 3.90 (s, 3H), 3.27 (t, J=7.2 Hz,2H).

Example 26:5-Amino-1-(4,4-dimethylcyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(4,4-dimethylcyclohexylidene)amino]carbamate

Following general procedure E, 4,4-dimethylcyclohexanone (0.79 mmol)gave the titled compound (0.78 mmol) as an off-white powder. ¹H NMR (400MHz, CDCl₃, δ): 7.49 (br s, 1H), 2.45-2.39 (m, 2H), 2.26-2.20 (m, 2H),1.55-1.44 (m, 13H), 1.02 (s, 6H).

5-Amino-3-(4-bromophenyl)-1-(4,4-dimethylcyclohexyl)pyrazole-4-carbonitrile

General procedure O, tert-butylN-[(4,4-dimethylcyclohexylidene)amino]carbamate (0.78 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) gavethe titled compound (0.36 mmol) as an off-white powder. UPLC-MS (ES⁺,Short acidic): 2.33 min, m/z 375.1 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(4,4-dimethylcyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(4,4-dimethylcyclohexyl)pyrazole-4-carbonitrile(0.13 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.15 mmol) gavethe titled compound (0.13 mmol) as an off-white powder. UPLC-MS (ES⁺,Short acidic): 1.99 min, m/z 458.3 [M+H]⁺

5-Amino-1-(4,4-dimethylcyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(4,4-dimethylcyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.07 mmol) afforded, after further purification by reverse-phasechromatography eluting with 20-60% MeCN in water containing 0.1% formicacid additive, the titled compound (0.02 mmol) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.74 min, m/z 476.3 [M+H]⁺. UPLC-MS (ES⁺, Longacidic): 4.04 min, m/z 476.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.74(t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H), 7.52-7.38 (m, 5H), 7.16(d, J=8.3 Hz, 1H), 7.08-7.01 (m, 1H), 6.31 (s, 2H), 4.55 (d, J=6.1 Hz,2H), 4.10-3.98 (m, 1H), 3.91 (s, 3H), 2.00-1.86 (m, 2H), 1.71-1.60 (m,2H), 1.52-1.42 (m, 2H), 1.42-1.29 (m, 2H), 0.95 (s, 6H)

Example 27:5-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

8-Methyl-1,4-dioxaspiro[4.5]decan-8-ol

A solution of methylmagnesium bromide (2.2 M in diethyl ether, 2.82mmol) was added to a solution of 1,4-cyclohexanedione monoethyleneacetal (2.56 mmol) in THF (5 mL), cooled to 0° C. The reaction mixturewas stirred at RT for 2 h, and then quenched with a saturated solutionof aqueous ammonium chloride. The layers were partitioned between DCM(20 mL) and water (20 mL). The aqueous layer was extracted with DCM(×3). The combined organic extracts were filtered over a phase separatorand concentrated under reduced pressure to give crude the titledcompound (2.50 mmol) as a clear oil. ¹H NMR (400 MHz, CDCl₃, δ):4.02-3.91 (m, 4H), 1.96-1.84 (m, 2H), 1.78-1.65 (m, 4H), 1.65-1.56 (m,2H), 1.29 (s, 3H), 1.15 (s, 1H)

4-Hydroxy-4-methyl-cyclohexanone

Following general procedure J, 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol(2.50 mmol) in THF (2.5 mL) afforded the titled compound crude (2.50mmol) as a brown oil. ¹H NMR (400 MHz, CDCl₃, δ): 2.71-2.59 (m, 2H),2.23-2.12 (m, 2H), 1.96-1.86 (m, 2H), 1.85-1.73 (m, 2H), 1.31 (s, 3H),1.23 (s, 1H)

tert-Butyl N-[(4-hydroxy-4-methyl-cyclohexylidene)amino]carbamate

Following general procedure E, 4-hydroxy-4-methyl-cyclohexanone (2.50mmol) gave the titled compound (1.36 mmol) as a clear oil. UPLC-MS (ES⁺,Short acidic): 1.21 min, m/z 243.1 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile

Following general procedure O, tert-butylN-[(4-hydroxy-4-methyl-cyclohexylidene)amino]carbamate (0.83 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.68 mmol) gave,after purification by flash column chromatography eluting with 55% EtOAcin heptane followed by 0-8% MeOH in DCM, the titled compound (isomer 1,0.43 mmol) as an off-white powder and the titled compound (isomer 2,0.09 mmol) as an off white solid. UPLC-MS (ES⁺, Short acidic; isomer 1):1.65 min, m/z 375.0 [M]⁺. UPLC-MS (ES⁺, Short acidic; isomer 2): 1.72min, m/z 375.1 [M]⁺

5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide

Following general procedure L,5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomer 1) (50 mg, 0.13 mmol) gave5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide(44 mg, 0.11 mmol, 84%) as an off-white powder. UPLC-MS (ES⁺, Shortacidic): 1.35 min, m/z 394.9 [M+2]⁺

5-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide(0.11 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.12 mmol) gavethe titled compound (0.09 mmol) as an off-white powder. UPLC-MS (ES⁺,Short acidic): 1.33 min, m/z 478.5 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):2.98 min, m/z 478.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.7, 1.7 Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J=8.3Hz, 1H), 7.08-7.01 (m, 1H), 6.29 (s, 2H), 4.55 (d, J=6.2 Hz, 2H), 4.12(s, 1H), 4.08-3.97 (m, 1H), 3.91 (s, 3H), 2.24-2.07 (m, 2H), 1.70-1.60(m, 2H), 1.60-1.50 (m, 2H), 1.50-1.37 (m, 2H), 1.15 (s, 3H)

Example 28:5-Amino-1-(4-benzyloxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

8-Benzyloxy-1,4-dioxaspiro[4.5]decane

Under N₂, sodium hydride, (60% dispersed in mineral oil, 1.90 mmol) wasadded to a solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.26 mmol) in THF(2.4 mL), cooled at 0° C. The reaction mixture was stirred at 0° C. for30 min, then, benzyl bromide (1.90 mmol) was added. The mixture wasallowed to stir at RT overnight, quenched with a saturated solution ofammonium chloride and partitioned. The aqueous layer was extracted withDCM (×3). The combined organic extracts were filtered over a hydrophobicfrit and concentrated under reduced pressure. Further purification byflash column chromatography on silica gel eluting with 30% ethyl acetatein heptane afforded the titled compound (0.81 mmol) as a clear oil.UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 249.0 [M+H]⁺

4-Benzyloxy cyclohexanone

General procedure J, 8-benzyloxy-1,4-dioxaspiro[4.5]decane (0.81 mmol)gave the titled compound crude (0.81 mmol) as a clear oil. ¹H NMR (400MHz, CDCl₃, δ): 7.44-7.29 (m, 5H), 4.63 (s, 2H), 3.88-3.82 (m, 1H),2.71-2.60 (m, 2H), 2.35-2.25 (m, 2H), 2.24-2.12 (m, 2H), 2.05-1.94 (m,2H)

tert-Butyl N-[(4-benzyloxycyclohexylidene)amino]carbamate

Following general procedure E, 4-benzyloxycyclohexanone (0.81 mmol) gavethe titled compound (0.81 mmol) as a clear oil. UPLC-MS (ES⁺, Shortacidic): 1.74 min, m/z 319.2 [M+H]⁺

5-Amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile

Following general procedure O, tert-butylN-[(4-benzyloxycyclohexylidene)amino]carbamate (0.81 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.68 mmol) gavethe titled compound (0.68 mmol) as an off-white powder. UPLC-MS (ES⁺,Short acidic, cis/trans mixture): 2.18 min and 2.20 min, m/z 453.1[M+2]⁺

5-Amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carboxamide

General procedure L,5-amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile(0.13 mmol) gave the titled compound (0.13 mmol) as a clear oil. UPLC-MS(ES⁺, Short acidic, cis/trans mixture): 1.91 min, m/z 471.0 [M+2]⁺

5-Amino-1-(4-benzyloxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure K,5-amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carboxamide(0.13 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.15 mmol) gavethe titled compound as a mixture of diastereoisomers (0.12 mmol) as awhite powder. UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z 554.5 [M+H]⁺,1.77 min, m/z 554.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 4.02 min, m/z554.3 [M+H]⁺, 4.11 min, m/z 554.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.73 (t, J=5.9 Hz, 1H), 7.76 (dd, J=7.6,1.6 Hz, 1H), 7.53-7.31 (m, 9H), 7.31-7.23 (m, 1H), 7.16 (d, J=8.4 Hz,1H), 7.08-7.01 (m, 1H), 6.34 (s, 1H), 6.32 (s, 1H), 4.59-4.46 (m, 4H),4.20-4.06 (m, 1H), 3.90 (s, 3H), 3.69-3.62 (m, 0.5), 3.46-3.35 (m,0.5H), 2.20-1.94 (m, 3H), 1.93-1.73 (m, 2H), 1.68-1.46 (m, 2H),1.46-1.25 (m, 1H)

Example 29:5-Amino-1-cyclopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-cyclopropyl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.46 mmol) andcyclopropylhydrazine hydrochloride (0.55 mmol) gave, after furtherpurification by flash column chromatography on silica gel eluting with0-10% MeOH in DCM, the titled compound (0.34 mmol) as a white solid.UPLC-MS (ES+, Short acidic): 1.73 min, m/z 303.0 [M]⁺

N-[[4-(5-amino-4-cyano-1-cyclopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-cyclopropyl-pyrazole-4-carbonitrile (0.32mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.45 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.34 mmol) as crude brown solid. UPLC-MS (ES+, Short acidic):1.51 min, m/z 388.2 [M+H]⁺

5-Amino-1-cyclopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-cyclopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.32 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.15 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.32min, m/z 406.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.95 min, m/z 406.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.75 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.7,1.3 Hz, 1H), 7.53-7.34 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.06-7.03 (m,1H), 6.33 (s, 2H), 4.55 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 3.32-3.24 (m,1H), 1.04-0.92 (m, 4H)

Example 30:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-methyl-pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-methyl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.14 mmol) andmethylhydrazine (1.37 mmol) gave, after further purification by flashcolumn chromatography on silica gel eluting with 0-10% MeOH in DCM, aninseparable mixture of regioisomers the titled compound (0.47 mmol) as awhite solid. UPLC-MS (ES⁺, Short acidic): 1.57 min and 1.67 min, m/z277.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-methyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K, a mixture of5-amino-3-(4-bromophenyl)-1-methyl-pyrazole-4-carbonitrile and3-amino-5-(4-bromophenyl)-1-methyl-pyrazole-4-carbonitrile (0.43 mmol)and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.37mmol) gave, after further purification by flash column chromatography onsilica gel eluting with 10-100% EtOAc in heptane, the titled compound(0.11 mmol) as an white solid. UPLC-MS (ES⁺, Short acidic): 1.54 min,m/z 362.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-methyl-pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-methyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.09 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.05 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.24min, m/z 380.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.76 min, m/z 380.2[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.75 (t, J=6.2 Hz, 1H), 7.76 (dd, J=7.8,1.7 Hz, 1H), 7.51-7.39 (m, 5H), 7.16 (dd, J=8.4, 0.9 Hz, 1H), 7.07-7.03(m, 1H), 6.28 (s, 2H), 4.55 (d, J=6.2 Hz, 2H), 3.90 (s, 3H), 3.56 (s,3H)

Example 31:5-Amino-1-(2-hydroxyethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2-hydroxyethyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.14 mmol) and2-hydroxyethylhydrazine (1.37 mmol) gave, after purification by flashcolumn chromatography on silica gel eluting with 10-100% EtOAc inheptane gave the titled compound (0.40 mmol) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.60 min, m/z 307.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2-hydroxyethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2-hydroxyethyl)pyrazole-4-carbonitrile(0.35 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.49 mmol) gave,after further purification by flash column chromatography on silica geleluting with 0-10% MeOH in DCM, the titled compound (0.22 mmol) as lightbrown solid. UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 392.1 [M+H]⁺

5-Amino-1-(2-hydroxyethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2-hydroxyethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.21 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.09 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.20min, m/z 410.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.66 min, m/z 410.2[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.2 Hz, 1H), 7.76 (dd, J=7.8,1.7 Hz, 1H), 7.52-7.39 (m, 5H), 7.16 (m, 1H), 7.05 (m, 1H), 6.21 (s,2H), 5.00-4.94 (m, 1H), 4.56 (d, J=6.2 Hz, 2H), 3.98 (t, J=5.9 Hz, 2H),3.90 (s, 3H), 3.71 (q, J=5.71 Hz, 2H).

Example 32:5-amino-1-(3-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(3-fluorophenyl)pyrazole-4-carbonitrile

General procedure H, (3-fluorophenyl)hydrazinium chloride (0.68 mmol)and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol)gave, after purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane, the titled compound (0.22 mmol,38% yield) as a light brown solid. UPLC-MS (ES⁺, Short acidic): 1.97min, m/z 357.1 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(3-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3-fluorophenyl)pyrazole-4-carbonitrile(0.22 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.30 mmol) gave,after further purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane, titled compound (0.05 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 442.2 [M+H]⁺

5-Amino-1-(3-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.05 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.03 mmol) was obtained as a white solid. UPLC-MS (ES⁺, Shortacidic): 1.54 min, m/z 460.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.52min, m/z 460.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz,1H), 7.76 (dd, J=7.5, 1.6 Hz, 1H), 7.62-7.55 (m, 3H), 7.52-7.45 (m, 5H),7.26 (t, J=8.6 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.05 (t, J=7.58 Hz, 1H),6.62 (s, 2H), 4.57 (d, J=6.1 Hz, 2H), 3.91 (s, 3H).

Example 33:5-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide

Following general procedure L,5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomer 2) (0.09 mmol) gave crude the titled compound (0.09 mmol) as anoff-white powder. UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 395.1[M+2]⁺

5-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide(0.09 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.09 mmol) gavethe titled compound (0.04 mmol) as an off-white powder. UPLC-MS (ES⁺,Short acidic): 1.30 min, m/z 478.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):2.94 min, m/z 478.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.6,1.7 Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.08-7.00 (m,1H), 6.33 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 4.42 (s, 1H), 4.18-4.05 (m,1H), 3.90 (s, 3H), 1.92-1.71 (m, 4H), 1.70-1.60 (m, 2H), 1.60-1.48 (m,2H), 1.17 (s, 3H).

Example 34a: (Isomer 1) and 34b (Isomer 2):5-Amino-1-(4-hydroxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(4-hydroxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Palladium (10 wt. % on carbon powder, dry) (0.33 mmol) was added to asolution of5-amino-1-(4-benzyloxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(0.13 mmol) in MeOH (1.3 mL) and ammonium formate (0.40 mmol). Thereaction mixture was stirred at 60° C. for 2 h then ammonium formate(1.34 mmol) was added and the mixture was stirred at 60° C. for 1 h.Acetic acid (0.5 mL) was added and the reaction mixture was allowed tostir at 60° C. for another 14 h, cooled to RT and filtered over a plugof Celite®. The plug was washed with DCM and the filtrate concentratedunder reduced pressure. The residue was basified with a saturatedsolution of sodium bicarbonate and extracted with DCM (×3). The combinedorganic extracts were filtered over a hydrophobic frit and concentratedunder reduced pressure. Further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM afforded thetitled compound (isomer 1, 0.02 mmol) as a white solid and the titledcompound (isomer 2, 0.09 mmol) as a brown solid.

UPLC-MS (ES⁺, Short acidic; isomer 1): 1.27 min, m/z 464.3 [M+H]⁺.UPLC-MS (ES⁺, Long acidic; isomer 1): 2.84 min, m/z 464.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □) (isomer 1): 8.74 (t, J=6.0 Hz, 1H), 7.76 (dd,J=7.6, 1.7 Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.08-7.00(m, 1H), 6.30 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 4.40 (d, J=2.6 Hz, 1H),4.13-4.02 (m, 1H), 3.90 (s, 3H), 3.86 (br s, 1H), 2.23-2.07 (m, 2H),1.84-1.72 (m, 2H), 1.61-1.47 (m, 4H).

UPLC-MS (ES⁺, Short acidic; isomer 2): 1.26 min, m/z 464.3 [M+H]⁺.UPLC-MS (ES⁺, Long acidic; isomer 2): 2.82 min, m/z 464.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □) (isomer 2): 8.74 (t, J=6.1 Hz, 1H), 7.76 (dd,J=7.7, 1.7 Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.08-7.00(m, 1H), 6.33 (s, 2H), 4.63 (d, J=4.5 Hz, 1H), 4.55 (d, J=6.1 Hz, 2H),4.13-4.01 (m, 1H), 3.90 (s, 3H), 3.51-3.39 (m, 1H), 1.96-1.86 (m, 2H),1.86-1.74 (m, 4H), 1.39-1.25 (m, 2H).

Example 35:5-Amino-1-cyclobutyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-(cyclobutylideneamino)carbamate

To a solution of cyclobutanone (2.0 mmol) in heptane (2 mL) was addedtert-butyl carbazate (2.2 mmol) and the reaction was heated to refluxand stirred for 2 h. Volatiles were removed under reduced pressure togive the titled compound (2.0 mmol, 100% yield) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 185.0 [M+H]⁺

Cyclobutylhydrazine hydrochloride

tert-Butyl N-(cyclobutylideneamino)carbamate (0.27 mmol) was dissolvedin THF (5 mL) and dimethylsulfide borane (0.46 mmol) was added. Thereaction was stirred at RT for 1 h. As TLC showed consumption of thestarting material, the solvent was removed in vacuo. The residue wasdissolved in hydrogen chloride-methanol solution (7.6 mL), the reactionwas heated to reflux and stirred overnight. Evaporation of the solventafforded the titled compound (0.27 mmol) as a yellowish gum which wasused without any further purification. ¹H NMR (400 MHz, DMSO-d₆, □):3.66-3.54 (m, 1H), 2.16-1.97 (m, 4H), 1.83-1.64 (m, 2H).

5-Amino-3-(4-bromophenyl)-1-cyclobutyl-pyrazole-4-carbonitrile

General procedure H, cyclobutylhydrazine hydrochloride (0.25 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.21 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 20-80% EtOAc in heptane, the titled compound (0.14 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.95 min, m/z 317.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-cyclobutyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-cyclobutyl-pyrazole-4-carbonitrile (0.14mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.19 mmol) gave the titled compound (0.13 mmol) as a white powder.UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z 402.2 [M+H]⁺

5-Amino-1-cyclobutyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-cyclobutyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.05 mmol) gave the titled compound (0.03 mmol) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 420.3 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 3.29 min, m/z 420.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=6.2 Hz, 1H), 7.76 (dd, J=7.9,2.2 Hz, 1H), 7.50-7.41 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 6.30 (s, 2H), 4.81-4.73 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.91(s, 3H), 2.33-2.26 (m, 4H), 1.78-1.69 (m, 2H).

Example 36:5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

tert-Butyl N-tetrahydrofuran-3-ylideneamino]carbamate

To a solution of dihydro(3(2H)-furanone (1.95 mmol) in ethanol (2 mL)was added tert-butyl carbazate (2.35 mmol) and the reaction was heatedto reflux and stirred overnight. Volatiles were removed under reducedpressure to give the titled compound (1.95 mmol) as a white solid. ¹HNMR (400 MHz, CDCl₃, δ, mixture of isomers): 7.25 (s, 0.75H), 7.12 (s,0.25H), 4.34 (t, J=1.2 Hz, 1.5H), 4.24 (t, J=1.2 Hz, 0.5H), 4.12 (t,J=6.9 Hz, 1.5H), 4.02 (t, J=6.9 Hz, 0.5H), 2.78 (td, J=6.9, 1.2 Hz,0.5H), 2.48 (td, J=6.9, 1.2 Hz, 1.5H), 1.54 (s, 7.5H), 1.53 (s, 1.5H).

Tetrahydrofuran-3-ylhydrazine hydrochloride

tert-Butyl N-[tetrahydrofuran-3-ylideneamino]carbamate (0.25 mmol) wasdissolved in THF (5 mL) and dimethylsulfide borane (0.42 mmol) wasadded. The reaction was stirred at RT for 1 h until TLC showed completeconsumption of the starting material. Solvent was removed in vacuo. Theresidue was dissolved with a hydrogen chloride solution in MeOH (1.25 M,6.99 mL), and the reaction was heated to reflux and stirred overnight.Evaporation of the solvent afforded the titled compound (0.25 mmol) as ayellowish gum which was used without any further purification. ¹H NMR(400 MHz, DMSO-d₆, δ): 3.86-3.59 (m, 6H), 2.11-1.96 (m, 1H), 1.95-1.84(m, 1H).

5-Amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H, tetrahydrofuran-3-ylhydrazine hydrochloride (0.23mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.19mmol) gave, after purification by flash column chromatography on silicagel eluting with 20-80% EtOAc in heptane, the titled compound (0.09mmol) as a light brown solid. UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z333.1 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.10 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.14 mmol) gavethe titled compound (0.06 mmol) as a white solid. UPLC-MS (ES⁺, Shortacidic): 1.51 min, 418.2 m/z [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.06 mmol) gave the titled compound (0.03 mmol) as a white powder.UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 458.2 [M+Na]⁺. UPLC-MS (ES⁺,Long acidic): 2.95 min, m/z 436.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □):8.74 (t, J=5.8 Hz, 1H), 7.75 (dd, J=7.4, 1.8 Hz, 1H), 7.50-7.40 (m, 5H),7.16 (d, J=7.7 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz, 1H), 6.40 (s, 2H),4.97-4.90 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 4.00-3.94 (m, 2H), 3.90 (s,3H), 3.83-3.78 (m, 2H), 2.28-2.24 (m, 2H)

Example 37:5-amino-1-[(1S*,3S*)-3-chlorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-[(1S*,3S*)-3-chlorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Thionyl chloride (0.67 mmol) was added to a solution of5-amino-1-[(1<S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(0.22 mmol) in DCM (3 mL), cooled to 0° C. The reaction was allowed torise to RT and stirred for 48 h at this temperature. The mixture wasthen concentrated and the resulting residue was then purified byreverse-phase chromatography eluting with 30-80% MeCN in watercontaining 0.1% formic acid additive to afford the titled compound (0.07mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 468.1[M]⁺. UPLC-MS (ES⁺, Long acidic): 3.62 min, m/z 468.1 [M]⁺.

¹H NMR (400 MHz, CDCl₃, δ): 8.29-8.20 (m, 2H), 7.56-7.42 (m, 5H),7.15-7.11 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 5.46 (br.s, 2H), 5.15 (br.s,2H) 4.80-4.70 (m, 3H), 4.68-4.63 (m, 1H), 3.95 (s, 3H), 2.77-2.67 (m,1H), 2.55-2.37 (m, 3H), 2.23-2.11 (m, 1H), 2.11-2.01 (m, 1H)

Example 38:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3R)-3-piperidyl]methyl]pyrazole-4-carboxamide

tert-Butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate

To a stirred solution of(3R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (0.87 mmol) indry THF (10 mL) at RT was added dropwise borane-tetrahydrofuran (1:1,2.62 mmol). The reaction was stirred for 4 h, quenched with a saturatedNH₄Cl solution (2 mL) and partitioned. The aqueous phase was extractedwith EtOAc. The combined organic extracts were washed with brine, driedover sodium sulfate and concentrated under reduced pressure. Furtherpurification by flash column chromatography on silica gel eluting with0-100% EtOAc in heptane afforded the titled compound (0.84 mmol) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆, □): 4.52-4.46 (m, 1H), 4.01-3.86(m, 1H), 3.83-3.75 (m, 1H), 3.30-3.26 (m, 1H), 3.22-3.16 (m, 1H),2.75-2.63 (m, 1H), 1.70-1.62 (m, 1H), 1.61-1.53 (m, 1H), 1.50-1.40 (m,1H), 1.38 (s, 9H), 1.36-1.21 (m, 2H), 1.13-1.01 (m, 1H).

tert-Butyl (3R)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate

General procedure I, tert-butyl(3R)-3-(hydroxymethyl)piperidine-1-carboxylate (0.84 mmol) andmethanesulfonyl chloride (0.88 mmol) gave, after purification by flashcolumn chromatography on silica gel eluting with 0-50% EtOAc in heptane,the titled compound (0.58 mmol) as a colourless oil. UPLC-MS (ES⁺, Shortacidic): 1.71 min, m/z 316.1 [M+Na]⁺

tert-Butyl(3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl)piperidine-1-carboxylate

General procedure N,5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.29 mmol) and tert-butyl(3R)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (0.58 mmol)gave, after purification by flash column chromatography on silica gel,the titled compound (0.19 mmol) and tert-butyl(3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidine-1-carboxylateas a mixture of regioisomers. UPLC-MS (ES⁺, Short acidic): 1.58 and 1.60min, m/z 563.3 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3R)-3-piperidyl]methyl]pyrazole-4-carboxamide

A mixture of regioisomers tert-butyl(3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]piperidine-1-carboxylate(0.19 mmol) and tert-butyl(3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidine-1-carboxylatewas dissolved in DCM (5 mL) and trifluoroacetic acid (4.7 mmol) wasadded. The reaction was stirred at RT overnight. The solvent was removedin vacuo. The residue was taken up with MeOH and passed through a SPESCX cartridge, eluting with 0-100% 1 N ammonia in MeOH. Furtherpurification by mass-directed semi-preparative HPLC gave the titledcompound (0.02 mmol). UPLC-MS (ES⁺, Short acidic): 1.10 min, m/z 463.2[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.41 min, m/z 463.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □): 8.74 (t, J=6.0 Hz, 1H), 8.38 (s, 2H), 7.76 (dd,J=7.4, 1.5 Hz, 1H), 7.51-7.40 (m, 5H), 7.16 (d, J=8.6 Hz, 1H), 7.04 (t,J=7.5 Hz, 1H), 6.37 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 3.83(d, J=7.1 Hz, 2H), 2.95-2.88 (m, 2H), 2.43-2.38 (m, 1H), 2.09-1.99 (m,1H), 1.70-1.64 (m, 2H), 1.46-1.36 (m, 1H), 1.24-1.15 (m, 1H).

Example 39:5-amino-1-(2-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2-fluorophenyl)pyrazole-4-carbonitrile

General procedure H, (2-fluorophenyl)hydrazine hydrochloride (0.68 mmol)and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol)gave, after purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane, the titled compound (0.29 mmol) asa brown solid. UPLC-MS (ES⁺, Short acidic): 1.88 min, m/z 357.1 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2-fluorophenyl)pyrazole-4-carbonitrile(0.29 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.40 mmol) gave,after further purification by flash column chromatography on silica geleluting with 10-100% EtOAc in heptane, the titled compound (0.23 mmol)as a red solid. UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 442.1 [M+H]⁺

5-Amino-1-(2-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.23 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.02 mmol) as an off white solid. UPLC-MS (ES⁺, Short acidic):1.46 min, m/z 460.2 [M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 3.32 min, m/z 460.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.76 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.6, 1.6 Hz, 1H),7.60-7.53 (m, 4H), 7.50-7.43 (m, 4H), 7.38 (t, J=7.75 Hz, 1H), 7.16 (d,J=8.4 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 6.42 (s, 2H), 4.57 (d, J=6.0 Hz,2H), 3.91 (s, 3H).

Example 40: Ethyl4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate

Ethyl 4-(tert-butoxycarbonylhydrazono)cyclohexanecarboxylate

General procedure E, ethyl 4-oxocyclohexanecarboxylate (3.14 mmol) gavethe titled compound (2.96 mmol) as a clear oil. UPLC-MS (ES⁺, Shortacidic): 1.52 min, m/z 285.1 [M+H]⁺

Ethyl4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylate

General procedure O, ethyl4-(tert-butoxycarbonylhydrazono)cyclohexanecarboxylate (1.93 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.63 mmol) gavethe titled compound (1.56 mmol, mixture of cis/trans isomers) as a whitepowder. UPLC-MS (ES⁺, Short acidic): 2.00 min, m/z 419.1 [M+2]⁺, 2.06min, m/z 419.1 [M+2]⁺

Ethyl4-[5-amino-3-(4-bromophenyl)-4-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylate

General procedure L, ethyl4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylate(0.91 mmol) gave the titled compound (0.91 mmol, mixture of cis/transisomers) as an off-white powder. UPLC-MS (ES⁺, Short acidic): 1.70 min,m/z 437.1 [M+2]⁺, 1.72 min, m/z 437.1 [M+2]⁺

Ethyl4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.00 mmol) andethyl4-[5-amino-3-(4-bromophenyl)-4-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylate(0.91 mmol) gave the titled compound (0.68 mmol, mixture of cis/transisomers) as a white powder. UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z520.3 [M+H]⁺, 1.59 min, m/z 520.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):3.63 min, m/z 520.3 [M+H]⁺, 3.67 min, m/z 520.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □) 8.73 (t, J=6.1 Hz, 1H), 7.79-7.73 (m, 1H), 7.52-7.38 (m,5H), 7.16 (d, J=8.4 Hz, 1H), 7.08-7.00 (m, 1H), 6.35 (s, 0.8H), 6.33 (s,1.2H), 4.55 (d, J=6.1 Hz, 2H), 4.18-4.03 (m, 3H), 3.90 (s, 3H),2.73-2.29 (m, 1H), 2.22-2.11 (m, 1H), 2.06-1.95 (m, 1H), 1.92-1.42 (m,6H), 1.23-1.15 (m, 3H)

Example 41:5-amino-1-[(1S*,3S*)-3-fluorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-[(1S*,3S*)-3-fluorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

(Diethylamino)sulfur trifluoride (0.96 mmol) was added dropwise to asolution of5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(0.24 mmol) in DCM (2 mL), cooled to −20° C. The reaction mixture wasallowed to return to RT and then stirred for a further 2 h. The mixturewas diluted with DCM and then quenched with saturated aqueous NaHCO₃.The aqueous layer was extracted with DCM. The organic layers werecombined, filtered over a hydrophobic frit and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel, eluting with 0-10% MeOH in DCM. Furtherpurification by reverse-phase chromatography eluting with 30-80% MeCN inwater containing 0.1% formic acid additive afforded the titled compound(0.02 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z452.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.39 min, m/z 452.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, □): 8.72 (t, J=6.1 Hz, 1H), 7.74 (dd, J=1.8,7.7, 1H), 7.50-7.37 (m, 5H), 7.14 (d, J=8 Hz, 1H), 7.03 (td, J=1.0, 7.5Hz, 1H), 6.39 (br s, 2H), 5.32 (d, J=53.6 Hz, 1H), 4.94-4.83 (m, 1H),4.53 (d, J=6.1 Hz, 2H), 3.89 (s, 3H), 2.31-1.79 (m, 6H)

Example 42:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidyl]methyl]pyrazole-4-carboxamide

tert-Butyl (3S)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate

General procedure I, tert-butyl(3S)-3-(hydroxymethyl)piperidine-1-carboxylate (0.82 mmol) andmethanesulfonyl chloride (0.86 mmol) gave, after purification by flashcolumn chromatography on silica gel eluting with 0-50% EtOAc in heptane,the titled compound (0.72 mmol) as a colourless oil. UPLC-MS (ES⁺, Shortacidic): 1.71 min, m/z 316.1 [M+Na]⁺

tert-Butyl(3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]piperidine-1-carboxylate

General procedure N,5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide(0.23 mmol) and tert-butyl (3S)-3-(methyl sulfonyloxymethyl)piperidine-1-carboxylate (0.47 mmol) gave, after purificationby flash column chromatography on silica gel, the titled compound andtert-butyl(3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidine-1-carboxylate(0.13 mmol) as a beige solid mixture of regioisomers. UPLC-MS (ES⁺,Short acidic): 1.59 and 1.60 min, m/z 563.3 [M+H]⁺

3-Amino-5-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidyl]methyl]pyrazole-4-carboxamideand5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidyl]methyl]pyrazole-4-carboxamide

tert-Butyl(3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]piperidine-1-carboxylateand tert-butyl(3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidine-1-carboxylate(0.13 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (3.3mmol) was added. The reaction was stirred at RT overnight. The solventwas removed under reduced pressure. The residue was taken up with MeOHand passed through a SPE SCX cartridge, eluting with 0-100% 1 M ammoniain MeOH. The mixture of regioisomers was then purified by mass-directedsemi-preparative HPLC to give5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidyl]methyl]pyrazole-4-carboxamide(0.01 mmol). UPLC-MS (ES⁺, Short acidic): 1.09 min, m/z 463.2 [M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 2.41 min, m/z 463.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.74 (t, J=5.8 Hz, 1H), 8.42 (s, 2H), 7.75(dd, J=7.5, 1.5 Hz, 1H), 7.50-7.40 (m, 5H), 7.16 (d, J=8.2 Hz, 1H),7.06-7.03 (m, 1H), 6.36 (s, 2H), 4.55 (d, 7=5.8 Hz, 2H), 3.90 (s, 3H),3.82 (d, J=7.1 Hz, 2H), 2.91-2.86 (m, 2H), 2.40-2.38 (m, 2H), 2.03-1.99(m, 1H), 1.69-1.62 (m, 2H), 1.40-1.34 (m, 1H), 1.21-1.15 (m, 1H).

Example 43:5-amino-1-(4-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(4-fluorophenyl)pyrazole-4-carbonitrile

General procedure H, 4-fluorophenyl)hydrazine hydrochloride (0.68 mmol)and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol)gave, after purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane, the titled compound (0.41 mmol) asa light brown solid. UPLC-MS (ES⁺, Short acidic): 1.94 min, m/z 359.0[M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(4-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(4-fluorophenyl)pyrazole-4-carbonitrile(0.41 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.57 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 0-100% EtOAc in heptane, the titled compound (0.38 mmol) as a brownsolid. UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 442.2 [M+H]⁺

5-Amino-1-(4-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(4-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.33 mmol) gave, after further purification by mass-directedsemi-preparative HPLC, the titled compound (0.03 mmol) was obtained as awhite solid. UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 460.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.45 min, m/z 460.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.1 Hz, 1H), 7.77 (dd, J=7.7,1.7 Hz, 1H), 7.66-7.63 (m, 2H), 7.56-7.54 (m, 2H), 7.51-7.44 (m, 3H),7.41 (m, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.07-7.03 (m, 1H), 6.47 (s, 2H),4.57 (d, J=6.1 Hz, 2H), 3.91 (s, 3H).

Example 44:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(p-tolyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(p-tolyl)pyrazole-4-carbonitrile

General procedure H, p-tolylhydrazine hydrochloride (0.34 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.29 mmol) gave,after further purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane, the titled compound (0.29 mmol) asan orange solid. UPLC-MS (ES⁺, Short acidic): 2.00 min, m/z 353.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(p-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.30 mmol) and5-amino-3-(4-bromophenyl)-1-(p-tolyl)pyrazole-4-carbonitrile (0.21 mmol)gave, after further purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane, the titled compound(0.09 mmol) as a light brown solid. UPLC-MS (ES⁺, Short acidic): 1.75min, m/z 438.3 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(p-tolyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(p-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.09 mmol) gave, after further purification by preparative HPLC, thetitled compound (0.01 mmol) as an off-white solid. UPLC-MS (ES+, Shortacidic): 1.57 min, m/z 456.3 [M+H]⁺. UPLC-MS (ES+, Long acidic): 3.59min, m/z 456.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=5.9 Hz,1H), 7.77 (dd, J=7.7, 1.8 Hz, 1H), 7.55-7.53 (m, 2H), 7.51-7.44 (m, 5H),7.34-7.33 (m, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.07-7.03 (m, 1H), 6.41 (s,2H), 4.56 (d, J=6.2 Hz, 2H), 3.91 (s, 3H), 2.38 (s, 3H).

Example 45: Methyl4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoate

Methyl 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]benzoate

Following general procedure H, methyl 4-hydrazinylbenzoate hydrochloride(0.55 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(0.46 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-100% EtOAc in heptane, thetitled compound (0.27 mmol) as an orange solid. UPLC-MS (ES⁺, Shortacidic): 1.96 min, m/z 397.1 [M]⁺

Methyl4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoate

General procedure K, methyl4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]benzoate (0.27 mmol)and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.38mmol) gave, after further purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane, titled compound (0.20mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.70 min,482.3 m/z [M+H]⁺

Methyl4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoate

General procedure M, methyl4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoate(0.20 mmol) gave, after further purification by mass-directedpreparative HPLC, the titled compound (0.01 mmol) as an off-white solid.UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 500.3 [M+H]⁺. UPLC-MS (ES+,Long acidic): 3.52 min, m/z 500.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ):8.76 (t, J=6.3 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H),7.76 (dd, J=7.7, 1.7 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.50-7.45 (m, 3H),7.16 (d, J=8.4 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.7 (s, 2H), 4.58 (d,J=6.0 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H).

Example 46:5-amino-1-[(1S*,3S*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[(1S*)-3-[(1S*)-5-Amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclopentyl]2,2-dimethylpropanoate

To a solution of5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(160 mg, 0.36 mmol) in THF (1.8 mL) was added triphenylphosphine (0.71mmol) and trimethylacetic acid (0.53 mmol) and cooled to 0° C.Diisopropyl azodicarboxylate (0.71 mmol) was then added and the mixturestirred at this temperature for 15 min before allowing to rise to RT andstirring at this temperature for 48 h. The reaction was concentrated andthen purified by flash column chromatography on silica gel eluting with0-100% EtOAc in heptane to give titled compound (0.18 mmol). UPLC-MS(ES⁺, Short acidic): 1.73 min, 534.3 m/z [M+H]⁺

5-Amino-1-[(1S*,3S*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

To a solution of[(1S*,3S*)-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclopentyl]2,2-dimethylpropanoate(0.22 mmol) in THF (1 mL) was added lithium hydroxide (1.79 mmol). Thereaction mixture was then heated to 80° C. for 4 days, cooled anddiluted with DCM and partitioned with water. The mixture was passedthrough a phase separator and the aqueous layer was extracted with DCMseveral times. The organic layers were combined and concentrated. Theresulting residue was purified by flash column chromatography on silicagel eluting with 0-10% MeOH in DCM to give the titled compound (0.05mmol, 23% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.28min, m/z 450.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.86 min, m/z 450.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.72 (t, J=6.1 Hz, 1H), 7.74 (dd,J=1.8, 7.6 Hz, 1H), 7.50-7.45 (m, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.39 (d,J=8.3 Hz, 2H), 7.15 (d, J=8.5 Hz, 1H), 7.03 (td, J=1.0, 7.5 Hz, 1H),6.33 (br.s, 2H), 4.82 (quint, J=8.1, 15.3 Hz, 1H), 4.62 (d, J=3.4 Hz,1H), 4.54 (d, J=6.1 Hz, 2H), 4.35-4.28 (m, 1H), 3.89 (s, 3H), 2.21-2.06(m, 2H), 2.04-1.86 (m, 2H), 1.85-1.74 (m, 1H), 1.58-1.48 (m, 1H)

Example 47:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(o-tolyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(o-tolyl)pyrazole-4-carbonitrile

Following general procedure H, o-tolylhydrazine hydrochloride (0.68mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57mmol) gave, after further purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane, the titled compound(0.53 mmol) as an orange solid. UPLC-MS (ES⁺, Short acidic): 1.94 min,m/z 355.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(o-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.30 mmol) and5-amino-3-(4-bromophenyl)-1-(o-tolyl)pyrazole-4-carbonitrile (0.21 mmol)gave, after further purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane, the titled compound(0.19 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z438.3 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(o-tolyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(o-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.19 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (0.06 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.50min, m/z 456.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.42 min, m/z 456.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.81 (t, J=6.0 Hz, 1H), 7.82 (dd, J=7.4,1.7 Hz, 1H), 7.60-7.58 (m, 2H), 7.56-7.49 (m, 5H), 7.45-7.40 (m, 2H),7.21 (d, J=8.2 Hz, 1H), 7.10 (t, J=7.3 Hz, 1H), 6.21 (s, 2H), 4.62 (d,J=6.0 Hz, 2H), 3.96 (s, 3H), 2.19 (s, 3H).

Example 48:5-amino-1-(3-hydroxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Sodium borohydride (836 mg, 22.10 mmol) was added to a solution of5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclohexyl)pyrazole-4-carboxamide(0.44 mmol) in MeOH (15 mL), cooled to 0° C. The reaction was allowed toreturn to RT and then heated to 60° C. for 14 h once the gas evolutionstopped. The reaction was cooled back to 0° C. and more sodiumborohydride (22.1 mmol) was added and the reaction heated again to 60°C. The mixture was then cooled and quenched with ammonium chloride, andthen extracted with EtOAc. The combined organic layer was dried oversodium sulfate and concentrated under reduced pressure. The resultingresidue was purified by reverse-phase chromatography to give the titledcompound (0.09 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.30min, m/z 464.3 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.90 min, m/z 464.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.5,1.8 Hz, 1H), 7.51-7.37 (m, 5H), 7.17-7.13 (m, 1H), 7.04 (td, J=7.6, 0.9Hz, 1H), 6.32 (s, 2H), 4.70 (d, J=4.9 Hz, 1H), 4.54 (d, J=6.0 Hz, 2H),4.17-4.06 (m, 1H), 3.90 (s, 3H), 3.56-3.45 (m, 1H), 2.05-1.96 (m, 1H),1.88-1.80 (m, 1H), 1.79-1.71 (m, 2H), 1.71-1.61 (m, 1H), 1.61-1.51 (m,1H), 1.39-1.21 (m, 1H), 1.15-1.01 (m, 1H).

Example 49:5-amino-1-[4-(hydroxymethyl)phenyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

To a solution of4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoicacid (0.05 mmol) in THF (3 mL) was added borane-dimethylsulfide (0.24mmol). The reaction mixture was stirred at RT for 5 h, quenched byaddition of a saturated solution of ammonium chloride (1 mL) andpartitioned. The aqueous layer was extracted with EtOAc. The combinedorganic extracts were dried over sodium sulfate, and concentrated underreduced pressure. The resulting residue was purified by mass-directedsemi-preparative HPLC to give the titled compound (0.01 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 472.3 [M+H]⁺. UPLC-MS(ES⁺, Long acidic): 2.95 min, m/z 472.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.75 (t, J=6.0 Hz, 1H), 7.78-7.72 (m, 1H), 7.59-7.51 (m,4H), 7.51-7.41 (m, 5H), 7.18-7.13 (m, 1H), 7.06-7.01 (m, 1H), 6.44 (s,2H), 5.35-5.27 (m, 1H), 4.60-4.52 (m, 4H), 3.90 (s, 3H).

Example 50:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(m-tolyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(m-tolyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.29 mmol) andm-tolylhydrazine (0.34 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-80% EtOAc in heptane, thetitled compound (0.21 mmol) as an orange solid. UPLC-MS (ES⁺, Shortacidic): 2.02 min, m/z 353.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(m-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.39 mmol) and5-amino-3-(4-bromophenyl)-1-(m-tolyl)pyrazole-4-carbonitrile (0.20 mmol)gave, after purification by flash column chromatography on silica geleluting with 10-100% EtOAc in heptane, the titled compound (0.19 mmol)as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 438.3[M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(m-tolyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(m-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.19 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.02mmol). UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 456.3 [M+H]⁺. UPLC-MS(ES⁺, Long acidic): 3.59 min, m/z 456.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.75 (t, J=6.2 Hz, 1H), 7.75 (dd, J=7.6,1.7 Hz, 1H), 7.57-7.52 (m, 2H), 7.51-7.37 (m, 6H), 7.24-7.19 (m, 1H),7.18-7.13 (m, 1H), 7.07-7.01 (m, 1H), 6.46 (s, 2H), 4.56 (d, J=6.2 Hz,2H), 3.90 (s, 3H), 2.39 (s, 3H).

Example 51:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-pyridyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(3-pyridyl)pyrazole-4-carbonitrile

General procedure H without triethylamine,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.42 mmol) and3-pyridylhydrazine (0.46 mmol) gave the titled compound (0.42 mmol) as awhite solid. LC-MS (ES⁺, Short acidic): 5.21 min, m/z 339.9 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(3-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3-pyridyl)pyrazole-4-carbonitrile (0.42mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.46 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-5% MeOH in DCM, the titled compound (0.30mmol) as an off-white solid. LC-MS (ES⁺, Short acidic): 4.44 min, m/z425.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-pyridyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(3-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.14 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.10mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 443.4[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.86 min, m/z 443.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.86 (d, J=2.5 Hz, 1H), 8.76 (t, J=6.2 Hz,1H), 8.60 (dd, J=4.9, 1.6 Hz, 1H), 8.06-8.03 (m, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.60-7.54 (m, 3H), 7.50-7.44 (m, 3H), 7.17-7.14 (m, 1H)7.03 (td, J=7.7, 1.1 Hz, 1H), 6.63 (br s, 2H), 4.56 (d, J=6.1 Hz, 2H),3.90 (s, 3H)

Example 52:5-amino-1-indan-2-yl-3-[4-[[ti-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-(indan-2-ylideneamino)carbamate

General procedure E, 2-indanone (1.14 mmol) and tert-butyl carbazate(1.36 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-80% EtOAc in heptane, the titled compound(0.89 mmol) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆, □): 9.54(s, 1H), 7.31-7.26 (m, 2H), 7.23-7.20 (m, 2H), 3.72 (s, 2H), 3.69 (s,2H), 1.47 (s, 9H).

Indan-2-ylhydrazine hydrochloride

tert-Butyl N-(indan-2-ylideneamino)carbamate (0.89 mmol) was dissolvedin THF (5 mL) and a borane dimethyl sulfide complex solution (2 M inTHF, 1.52 mmol) was added. The reaction was stirred at RT for 2 h untilTLC showed complete consumption of the starting material. The reactionwas quenched with a saturated aqueous solution of NH₄Cl and the layersseparated. The aqueous layer was extracted with DCM, and the combinedorganic extracts dried over sodium sulfate, and concentrated underreduced pressure. The residue was dissolved with a hydrogen chloridesolution (1.25 M in MeOH, 9.04 mmol), and the reaction was stirred at RTfor 16 h. The reaction was concentrated under reduced pressure to affordcrude indan-2-ylhydrazine hydrochloride (0.89 mmol). UPLC-MS: (ES⁺,Short acidic): 0.83 min, m/z 149.0 [M−HCl+H]⁺

5-Amino-3-(4-bromophenyl)-1-indan-2-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.68 mmol) andindan-2-ylhydrazine hydrochloride (0.82 mmol) gave, after purificationby flash column chromatography on silica gel eluting with 0-80% EtOAc inheptane, the titled compound (0.45 mol) as an orange solid. UPLC-MS:(ES⁺, Short acidic): 2.09 min, m/z 381.1 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-indan-2-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-indan-2-yl-pyrazole-4-carbonitrile (0.45mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.63 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane, the titled compoundbenzamide (0.34 mol) as an off-white solid. ¹H NMR (400 MHz, CDCl₃, □):8.27 (dd, J=7.8, 1.8 Hz, 1H), 8.24-8.19 (m, 1H), 7.91-7.89 (m, 2H),7.50-7.47 (m, 1H), 7.44-7.41 (m, 2H), 7.28-7.25 (m, 4H), 7.14-7.10 (m,1H), 7.01-6.99 (m, 1H), 5.09-5.01 (m, 1H), 4.73 (d, J=5.6 Hz, 2H), 4.27(s, 2H), 3.95 (s, 3H), 3.61 (dd, J=16.1, 7.1 Hz, 2H), 3.45 (dd, J=16.4,8.7 Hz, 2H).

5-Amino-1-indan-2-yl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-indan-2-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.11 mmol) gave, after purification by flash column chromatographyeluting with 0-10% MeOH in DCM, the titled compound (0.03 mmol) as awhite solid. UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 482.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.85 min, m/z 482.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.72 (t, J=6.0 Hz, 1H), 7.74 (dd, J=6.2,1.7 Hz, 1H), 7.50-7.38 (m, 5H), 7.25-7.23 (m, 2H), 7.19-7.14 (m, 3H),7.05-7.01 (m, 1H), 6.45 (s, 2H), 5.23-5.15 (m, 1H), 4.53 (d, J=6.0 Hz,2H), 3.89 (s, 3H), 3.39-3.28 (m, 4H).

Example 53:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-pyridyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2-pyridyl)pyrazole-4-carbonitrile

General procedure H without triethylamine,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.24 mmol) and2-hydrazinopyridine (1.36 mmol) gave the titled compound crude (1.24mmol, assumed quantitative) as a white solid. UPLC-MS (ES⁺, Shortacidic): 2.03 min, m/z 340.1 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2-pyridyl)pyrazole-4-carbonitrile (0.44mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.48 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.31mmol, 70% yield) as an off-white solid. UPLC-MS (ES⁺, Short acidic):1.77 min, m/z 425.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-pyridyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.31 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.10mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 443.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.67 min, m/z 443.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.3 Hz, 1H), 8.49-8.47 (m, 1H),8.01-7.96 (m, 1H), 7.88-7.86 (m, 1H), 7.76 (dd, J=7.7, 1.9 Hz, 1H), 7.69(br s, 2H), 7.59-7.56 (m, 2H), 7.51-7.46 (m, 3H), 7.34-7.31 (m, 1H),7.17-7.15 (m, 1H), 7.04 (td, J=7.6, 0.8 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H),3.91 (s, 3H).

Example 54:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-pyridyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(4-pyridyl)pyrazole-4-carbonitrile

Following general procedure H without triethylamine, 4-pyridylhydrazine(1.44 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(1.31 mmol) gave the titled compound crude (1.31 mmol) as a white solid.LC-MS (ES⁺, Short acidic): 4.66 min, m/z 341.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(4-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(4-pyridyl)pyrazole-4-carbonitrile (0.44mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(0.48 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.36mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z425.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-pyridyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(4-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.36 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, the titled compound (0.13mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.19 min, m/z 443.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.67 min, m/z 443.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.2 Hz, 1H), 8.69-8.67 (m, 2H),7.75 (dd, J=7.6, 1.8 Hz, 1H), 7.73-7.71 (m, 2H), 7.58-7.55 (m, 2H),7.50-7.45 (m, 3H), 7.17-7.14 (m, 1H), 7.03 (td, J=7.6, 1.0 Hz, 1H), 6.81(br s, 2H), 4.57 (d, J=6.0 Hz, 2H), 3.90 (s, 3H).

Example 55: ethyl3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 1)

Ethyl 3-(tert-butoxycarbonylhydrazono)cyclohexanecarboxylate

General procedure E, ethyl 3-oxocyclohexanecarboxylate (5.04 mmol) andtert-butyl carbazate (5.30 mmol) was stirred for 3 h at RT. The reactionmixture was quenched with MeOH and then concentrated under reducedpressure. The residue was diluted with DCM and washed with a saturatedaqueous solution of NH₄Cl. The organic layer was passed through a phaseseparator and concentrated under reduced pressure to give the titledcompound crude (3.77 mmol).

UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 285.1 [M+H]⁺

Ethyl3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylate

General procedure O, ethyl3-(tert-butoxycarbonylhydrazono)cyclohexanecarboxylate (3.77 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (3.04 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 0-100% EtOAc in heptane, the titled compound (isomer 1, 1.47 mmol)and the titled compound (isomer 2, 1.21 mmol). UPLC-MS (ES⁺, Shortacidic, Isomer 1):2.05 min, m/z 419.1[M+2]⁺. UPLC-MS (ES⁺, Short acidic,Isomer 2):2.11 min, m/z 419.1 [M+2]⁺

Ethyl3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 1)

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.11 mmol) andethyl3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylate(isomer 1, 0.72 mmol) was stirred at 80° C. for 16 h. The reactionmixture was filtered through a pad of Celite® and washed with DCM. Thesolution was diluted with water and extracted with DCM (×3). Thecombined organic layers were passed through a phase separator andconcentrated under reduced pressure to give the titled compound crude(isomer 1, 0.72 mmol).

UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 502.3 [M+H]⁺

Ethyl3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 1)

General procedure L, ethyl3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(isomer 1, 0.30 mmol), gave after purification by flash columnchromatography on silica gel eluting with 0-100% EtOAc in heptane, thetitled compound (isomer 1, 0.03 mmol, 10%). UPLC-MS (ES⁺, Short acidic):1.63 min, m/z 520.4 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.76 min, m/z520.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.75(dd, J=7.7, 1.8 Hz, 1H), 7.51-7.39 (m, 5H), 7.17-7.15 (m, 1H), 7.04 (td,J=7.6, 1.0 Hz, 1H), 6.27 (br s, 2H), 4.55 (d, J=6.2 Hz, 2H), 4.34-4.25(m, 1H), 4.15-4.09 (m, 2H), 3.90 (s, 3H), 3.01-2.94 (m, 1H), 2.11-2.04(m, 2H), 1.93-1.43 (m, 6H), 1.22 (t, J=6.9 Hz, 3H)

Example 56:5-anilino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Anilino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

To a suspension of5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.15mmol), phenylboronic acid (0.30 mmol) and copper(II) acetate (0.15 mmol)in DCM (1 mL) was added triethylamine (0.30 mmol). The reaction mixturewas stirred at RT for 16 h then concentrated under reduced pressure.Purification by flash column chromatography on silica gel eluting with20-60% EtOAc in heptane afforded the titled compound (0.10 mmol) as awhite solid. UPLC-MS (ES⁺, Short acidic): 2.30 min, m/z 407.0 [M]⁺

N-[[4-(5-Anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-anilino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.10mmol) gave, after purification by flash column chromatography on silicagel eluting with 20-80% EtOAc in heptane, the titled compound (0.09mmol) as a white powder. UPLC-MS (ES⁺, Short acidic): 2.04 min, m/z492.1 [M+H]⁺

5-Anilino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.09 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-3% MeOH in DCM, the titled compound (0.07mmol) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.88 min, m/z 510.2 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 4.47 min, m/z 510.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.71 (t, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.76(dd, J=7.6, 1.7 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.52-7.44 (m, 1H), 7.35(d, J=8.2 Hz, 2H), 7.22-7.09 (m, 4H), 7.08-6.95 (m, 2H), 6.80-6.72 (m,1H), 6.61 (d, J=7.7 Hz, 2H), 4.67-4.57 (m, 1H), 4.53 (d, J=6.0 Hz, 2H),3.91 (s, 3H), 2.01-1.76 (m, 6H), 1.63-1.48 (m, 2H).

Example57:5-amino-1-[4-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(Isomers 1, Example 57a, and 2, Example 57b)

5-Amino-1-[4-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

A solution of propylphosphonic anhydride (50 wt % in EtOAc, 0.14 mmol)was added to a solution of dimethylamine (2 M in THF, 0.92 mmol),N,N-diisopropylethylamine (0.27 mmol) and4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylicacid (0.09 mmol) in THF (0.50 mL). The reaction mixture was heated to40° C. and stirred for 16 h. Additional dimethylamine (2 M in THF, 0.92mmol), N,N-diisopropylethylamine (0.27 mmol) and a solution ofpropylphosphonic anhydride (50 wt % in EtOAc, 0.14 mmol) were addedsequentially and the reaction mixture was stirred at 40° C. for 48 h,and then cooled to RT. The reaction mixture was partitioned betweenwater and DCM. The aqueous layer was extracted with DCM (×3). Thecombined organic extracts were filtered over a hydrophobic frit and allvolatiles were removed under reduced pressure. Further purification byflash column chromatography on silica gel eluting with 0-8% MeOH in DCMgave the titled compound (isomer 1: 0.04 mmol, 42% yield) and the titledcompound (isomer 2: 0.02 mmol) were obtained as white solids. UPLC-MS(ES⁺, Short acidic; isomer 1): 1.40 min, m/z 519.3 [M+H]⁺. UPLC-MS (ES⁺,Long acidic; isomer 1): 3.71 min, m/z 519.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, 5, isomer 1): 8.73 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.7, 1.7 Hz,1H), 7.52-7.38 (m, 5H), 7.16 (d, J=8.4 Hz, 1H), 7.08-7.01 (m, 1H), 6.30(s, 2H), 4.55 (d, J=6.0 Hz, 2H), 4.21-4.10 (m, 1H), 3.91 (s, 3H), 3.00(s, 3H), 2.90-2.82 (m, 1H), 2.80 (s, 3H), 2.22-2.08 (m, 2H), 2.03-1.90(m, 2H), 1.74-1.64 (m, 2H), 1.64-1.53 (m, 2H).

UPLC-MS (ES⁺, Short acidic; isomer 2): 1.37 min, m/z 519.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic; isomer 2): 3.67 min, m/z 519.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ, isomer 2): 8.74 (t, J=6.1 Hz, 1H), 7.78-7.73 (m,1H), 7.52-7.37 (m, 5H), 7.16 (d, J=9.0 Hz, 1H), 7.08-7.01 (m, 1H), 6.35(s, 2H), 4.55 (d, J=6.0 Hz, 2H), 4.20-4.06 (m, 1H), 3.90 (s, 3H), 3.03(s, 3H), 2.81 (s, 3H), 2.73-2.61 (m, 1H), 1.96-1.82 (m, 4H), 1.82-1.73(m, 2H), 1.62-1.44 (m, 2H).

Example 58: ethyl3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 2)

Ethyl3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 2)

General procedure K, ethyl3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylate(isomer 2, 0.72 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.11 mmol) gavethe titled compound crude (isomer 2, 0.72 mmol, assumed quantitativeyield). UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 502.3 [M+H]⁺

Ethyl3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 2)

General procedure L, ethyl3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(isomer 2, 0.30 mmol) gave after purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM, the titledcompound (isomer 2, 0.02 mmol, 6% yield). UPLC-MS (ES⁺, Short acidic):1.78 min, m/z 520.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 4.23 min, m/z520.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 7.75(dd, J=7.7, 1.8 Hz, 1H), 7.52-7.38 (m, 5H), 7.17-7.15 (m, 1H), 7.04 (td,J=7.5, 0.7 Hz, 1H), 6.35 (br s, 2H), 4.55 (d, J=6.1 Hz, 2H), 4.23-4.12(m, 1H), 4.11-4.02 (m, 2H), 3.90 (s, 3H), 2.49-2.43 (m, 1H), 2.08-1.99(m, 1H), 1.94-1.66 (m, 5H), 1.51-1.36 (m, 1H), 1.35-1.21 (m, 1H), 1.17(t, J=7.0 Hz, 3H).

Example 59:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxoindan-1-yl)pyrazole-4-carboxamide

tert-Butyl N-[(3-oxoindan-1-ylidene)amino]carbamate

General procedure E, 1,3-indandione (1.37 mmol) and tert-butyl carbazate(1.44 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 10-50% EtOAc in heptane, the titled compound(0.86 mmol, 62% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆, □):10.19 (s, 1H), 7.90-7.88 (m, 1H), 7.81-7.76 (m, 1H), 7.63-7.59 (m, 1H),7.63-7.59 (m, 1H), 3.41 (s, 2H), 1.50 (s, 9H).

tert-Butyl N-[(3-oxoindan-1-yl)amino]carbamate

General procedure F, tert-butyl N-[(3-oxoindan-1-ylidene)amino]carbamate(0.75 mmol) gave the titled compound crude (0.57 mmol) as a colourlessoil. UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 285.1 [M+Na]⁺

[(3-Oxoindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate

To a solution of tert-butyl N-[(3-oxoindan-1-yl)amino]carbamate (0.57mmol) in DCM (5 mL) was added TFA (60 mmol). The reaction mixture wasstirred at RT for 1 h and concentrated under reduced pressure to affordthe titled compound crude (0.57 mmol). ¹H NMR (400 MHz, DMSO-d₆, □):7.89-7.35 (m, 4H), 5.21-5.10 (m, 1H), 3.19-3.05 (m, 1H), 2.88-2.75 (m,1H)

5-Amino-3-(4-bromophenyl)-1-(3-oxoindan-1-yl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.46 mmol) and[(3-oxoindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.10 mmol)gave, after purification by flash column chromatography on silica geleluting with 0-80% EtOAc in heptane, the titled compound (0.10 mmol) asan orange solid. UPLC-MS (ES⁺, Short acidic): 1.84 min, m/z 394.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3-oxoindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3-oxoindan-1-yl)pyrazole-4-carbonitrile(0.1 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.13 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 0-100% EtOAc in heptane, the titled compound (0.03 mmol) as a brownsolid. UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 478.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxoindan-1-yl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-oxoindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.03 mmol) gave, after purification by mass-directed semi-preparativeHPLC, the titled compound (0.02 mmol) as a beige solid. UPLC-CMS (ES⁺,Short acidic): 1.47 min, m/z 496.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):3.74 min, m/z 496.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.69 (t, J=6.0Hz, 1H), 7.75-7.71 (m, 3H), 7.56 (t, J=7.8 Hz, 1H), 7.49-7.47 (m, 2H),7.34 (s, 4H), 7.14 (d, J=6.0 Hz, 1H), 7.05-7.00 (m, 1H), 6.72 (s, 2H),6.20 (dd, J=7.7, 3.5 Hz, 1H), 4.50 (d, J=6.1 Hz, 2H), 3.87 (s, 3H), 3.25(dd, J=18.5, 7.6 Hz, 1H), 3.03 (dd, J=18.6, 3.4 Hz, 1H).

Example 60:1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)pyrazole-4-carboxamide

3-(4-Bromophenyl)-1-cyclopentyl-5-(methyleneamino)pyrazole-4-carbonitrile

To a solution of5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol) dissolved in MeOH (3 mL) was added paraformaldehyde (0.91 mmol)and sodium methoxide (25 wt % in MeOH, 1.81 mmol). The reaction mixturewas heated at reflux for 16 h. The reaction mixture was cooled to RT andthen partitioned between DCM and water. The aqueous layer was extractedwith DCM (×3), and the combined organic layers were passed through ahydrophobic frit and concentrated under reduced pressure to afford thetitled compound crude (0.30 mmol). UPLC-MS (ES⁺, Short acidic): 2.09min, m/z 377.0 [M+MeOH+2]⁺

3-(4-Bromophenyl)-1-cyclopentyl-5-(methylamino)pyrazole-4-carbonitrile

To a solution of3-(4-bromophenyl)-1-cyclopentyl-5-(methyleneamino)pyrazole-4-carbonitrile(0.30 mmol) in MeOH (3 mL) was added at 0° C. sodium borohydride (3.02mmol). The reaction mixture was stirred at RT for 72 h. Then it wascarefully quenched with a saturated aqueous solution of NH₄Cl. Theaqueous layer was then extracted with DCM (×3), and the combined organiclayers were passed through a hydrophobic frit and concentrated underreduced pressure. Purification by flash column chromatography on silicagel eluting with 20-60% EtOAc in heptane afforded the titled compound(0.20 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z347.0 [M+2]⁺

N-[[4-[4-Cyano-1-cyclopentyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-1-cyclopentyl-5-(methylamino)pyrazole-4-carbonitrile(0.20 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.22 mmol) gave,after purification by column chromatrography on silica gel eluting with20-60% EtOAc in heptane, the titled compound (0.11 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 430.1 [M+H]⁺

1-Cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)pyrazole-4-carboxamide

General procedure L,N-[[4-[4-cyano-1-cyclopentyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.11 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-4% MeOH in DCM and reverse phase columnchromatography eluting with 20-70% MeCN in water containing 0.1% formicacid, the titled compound (0.05 mmol) as a white solid. UPLC-MS (ES⁺,Short acidic): 1.67 min, m/z 448.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):4.30 min, m/z 448.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.71 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.54-7.46 (m, 3H), 7.37-7.34 (m,2H), 7.17-7.15 (m, 1H), 7.07-7.02 (m, 1H), 5.85-5.81 (m, 1H), 4.73-4.64(m, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 2.83 (d, J=5.6 Hz, 3H),2.06-1.89 (m, 4H), 1.89-1.76 (m, 2H), 1.69-1.54 (m, 2H).

Example 61:5-amino-1-(2,5-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2,5-difluorophenyl)pyrazole-4-carbonitrile

Following general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol) and(2,5-difluorophenyl)hydrazine (0.76 mmol) afforded, after purificationby flash column chromatography on silica gel eluting with 0-60% EtOAc inheptane, the titled compound (0.24 mmol) as a beige solid. UPLC-MS (ES⁺,Short acidic): 1.92 min, m/z 375.0 [M]⁺

N-[[4-[5-amino-4-cyano-1-(2,5-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,5-difluorophenyl)pyrazole-4-carbonitrile(0.24 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.26 mmol)afforded, after purification by flash column chromatography on silicagel eluting with 0-10% MeOH in DCM, the titled compound (0.24 mmol) as adark yellow gum. UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 460.2 [M+H]⁺

5-Amino-1-(2,5-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2,5-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.26 mmol) afforded, after purification by flash column chromatographyon silica gel eluting with 0-10% MeOH in DCM, the titled compound (0.03mmol, 10% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.50min, m/z 478.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.42 min, m/z 478.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 7.76 (dd, J=1.8,7.7 Hz, 1H), 7.57-7.41 (m, 8H), 7.17-7.15 (m, 1H), 7.07-7.01 (m, 1H),6.54 (s, 2H), 4.57 (d, J=6.1 Hz, 2H), 3.90 (s, 3H).

Example 62:5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]-3-methyl-phenyl]pyrazole-4-carboxamide

N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide

To a solution of 4-bromo-2-methyl-benzonitrile (5.10 mmol) dissolved inTHF (30 mL) was added, at 0° C., a borane tetrahydrofuran complexsolution (1 M in THF, 15.30 mmol). The solution was stirred at 0° C. for30 min before being warmed up to RT and stirred for 18 h. The reactionwas quenched dropwise with MeOH. Volatiles were concentrated underreduced pressure and the residue was partitioned with an aqueoussolution of NaOH (1 M) and EtOAc. The organic layer was dried oversodium sulfate, and concentrated under reduced pressure to give crude4-bromo-2-methyl-phenyl)methanamine, which was then dissolved in THF (20mL) and N,N-diisopropylethylamine (15.29 mmol) was added. The solutionwas cooled to 0° C. before 2-methoxybenzoyl chloride (5.61 mmol) wasadded. It was then stirred at 0° C. for 20 min before the reaction waswarmed up to RT and stirred for 16 h. The reaction was quenched with asaturated aqueous solution of NH₄Cl, worked-up, and purified (columnchromatography, 0-30% EtOAc in heptane) to give the titled compound(2.49 mmol). UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 336.1 [M+2]⁺

2-Methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

General procedure R,N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide (2.49 mmol) gavecrude the titled compound (2.49 mmol). UPLC-MS (ES⁺, Short acidic): 1.95min, m/z 382.2 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide

General procedure D,2-methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(2.04 mmol) gave, after purification (flash column chromatography,0-100% EtOAc in heptane) the titled compound (0.48 mmol). UPLC-MS (ES⁺,Short acidic): 1.40 min, m/z 362.3 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide

Cesium carbonate (0.63 mmol) was added to a mixture ofN-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide(0.48 mmol) and bromocyclopentane (0.53 mmol) in DMF (5 mL). Thereaction was heated to 80° C. for 16 h. Following work-up andpurification by flash column chromatography eluting with 0-1% MeOH inDCM, the titled compound (0.15 mmol) was obtained. UPLC-MS (ES⁺, Shortacidic): 1.81 min, m/z 430.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]-3-methyl-phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide(0.15 mmol) afforded, after purification by flash column chromatographyon silica gel eluting with 25-100% EtOAc in heptane, the titled compound(0.04 mmol). UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 448.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 4.04 min, m/z 448.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.61 (t, J=5.8 Hz, 1H), 7.73 (dd, J=7.7,1.7 Hz, 1H), 7.50-7.46 (m, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.30-7.23 (m,2H), 7.15 (d, J=8.3 Hz, 1H), 7.06-7.02 (m, 1H), 6.32 (s, 2H), 4.64-4.56(m, 1H), 4.50 (d, J=5.8 Hz, 2H), 3.89 (s, 3H), 2.36 (s, 3H), 2.03-1.84(m, 4H), 1.84-1.73 (m, 2H), 1.63-1.54 (m, 2H).

Example 63:5-amino-1-(3-hydroxyindan-1-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(3-hydroxyindan-1-yl)amino]carbamate

tert-Butyl N-[(3-oxoindan-1-ylidene)amino]carbamate (0.58 mmol) wasdissolved in THF (5 mL) and a borane dimethyl sulfide complex solution(2 M in THF, 3.45 mmol) was added. The reaction was stirred at RT for 14h. A saturated aqueous solution of NH₄Cl was added and following work-upand concentration the titled compound was obtained crude (0.57 mmol) asa pale orange solid.

UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 287.0 [M+Na]⁺

[(3-Hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate

To a solution of tert-butyl N-[(3-hydroxyindan-1-yl)amino]carbamate(0.57 mmol) in DCM (5 mL) was added trifluoroacetic acid (57 mmol) andthe reaction mixture was stirred at RT for 1 h. Volatiles wereconcentrated under reduced pressure to afford crude[(3-hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.57mmol). ¹H NMR (400 MHz, DMSO-d₆, □): 7.57-7.31 (m, 4H), 5.04-4.99 (m,1H), 2.83-2.78 (m, 1H), 2.09-1.98 (m, 1H)

5-Amino-3-(4-bromophenyl)-1-(3-hydroxyindan-1-yl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.46 mmol) and[(3-hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.55 mmol)gave, after purification by flash column chromatography on silica geleluting with 0-80% EtOAc in heptane, the titled compound (0.28 mmol) asan orange solid. UPLC-MS (ES⁺, Short acidic): 1.87 min, 396.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3-hydroxyindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3-hydroxyindan-1-yl)pyrazole-4-carbonitrile(0.28 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.39 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 0-100% EtOAc in heptane, the titled compound (0.25 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.75 min, m/z 480.1 [M+H]⁺

5-Amino-1-(3-hydroxyindan-1-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-hydroxyindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.10 mmol) gave, after purification by mass-directed semi-preparativeHPLC, the titled compound (0.05 mmol) as a beige solid. UPL-CMS (ES⁺,Short acidic): 1.60 min, m/z 498.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic):3.68 min, m/z 498.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.71 (t, J=6.0Hz, 1H), 7.74 (dd, J=7.7, 1.7 Hz, 1H), 7.50-7.36 (m, 6H), 7.34-7.30 (m,1H), 7.27-7.24 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.05-7.00 (m, 2H), 6.58(s, 2H), 5.76-5.71 (m, 1H), 5.68 (d, J=7.4 Hz, 1H), 5.06-5.01 (m, 1H),4.52 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 2.89-2.82 (m, 1H), 2.41-2.36 (m,1H)

Example 64:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.27 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.30 mmol)afforded, after purification by flash column chromatography on silicagel eluting with 0-10% MeOH in DCM, the titled compound (0.19 mmol, 72%yield) as a dark yellow gum. UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z432.3 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.33 mmol) afforded, after purification by flash column chromatographyon silica gel eluting with 0-10% MeOH in DCM followed by purification bySPE SCX cartridge eluting with MeOH, the titled compound (0.15 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 450.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.57 min, m/z 450.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.7,1.8 Hz, 1H), 7.50-7.40 (m, 5H), 7.17-7.15 (m, 1H), 7.06-7.02 (m, 1H),6.38 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 4.40-4.32 (m, 1H), 3.99-3.95 (m,2H), 3.90 (s, 3H), 3.46-3.40 (m, 2H), 2.03-1.94 (m, 2H), 1.79-1.76 (m,2H).

Example 65:5-amino-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

8-(Trifluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 1,4-cyclohexanedione monoethylene acetal (6.40 mmol) inanhydrous THF (20 mL) was added, under a nitrogen atmosphere at 0° C.,trimethyl(trifluoromethyl)silane (12.8 mmol) followed bytetrabutylammonium fluoride (1.0 M in THF, 13.4 mmol). The reactionmixture was then warmed to 25° C. and stirred for 2 h. A saturatedaqueous ammonium chloride solution (10 mL) was then added. The reactionmixture was stirred for 10 min and then concentrated under reducedpressure, work-up and purification gave the titled compound (5.83 mmol)as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃, □): 4.00-3.92 (m, 4H),1.97-1.88 (m, 4H), 1.83-1.79 (m, 2H), 1.69-1.67 (m, 2H).

4-Hydroxy-4-(trifluoromethyl)cyclohexanone

To a solution of 8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (5.84mmol) in acetone (29 mL) was added hydrochloric acid (4 M, 8.75 mmol).The reaction mixture was stirred for 18 h at RT and, following work-upand purification, gave the titled compound (5.12 mmol) as a white solid.¹H NMR (400 MHz, DMSO-d₆, □): 6.26 (br s, 1H), 2.62-2.52 (m, 2H),2.19-2.15 (m, 2H), 2.04-1.92 (m, 2H), 1.79-1.62 (m, 2H).

tert-ButylN-[[4-hydroxy-4-(trifluoromethyl)cyclohexylidene]amino]carbamate

General procedure E, 4-hydroxy-4-(trifluoromethyl)cyclohexanone (5.12mmol) gave the titled compound (2.29 mmol) as a white solid. ¹H NMR (400MHz, DMSO-d₆, □): 9.60 (br s, 1H), 6.02 (br s, 1H), 2.83-2.79 (m, 1H),2.42-2.37 (m, 2H), 2.24-2.20 (m, 1H), 1.85-1.79 (m, 2H), 1.70-1.55 (m,2H), 1.43 (s, 9H).

5-Amino-3-(4-bromophenyl)-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazole-4-carbonitrile

General procedure O, tert-butylN-[[4-hydroxy-4-(trifluoromethyl)cyclohexylidene]amino]carbamate (2.29mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.89mmol) gave the titled compound (0.12 mmol) as a yellow solid. UPLC-MS(ES⁺, Short acidic): 1.94 min, m/z 430.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazole-4-carbonitrile(0.42 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.46 mmol) gavethe titled compound (0.24 mmol) as an off-white solid. UPLC-MS (ES⁺,Short acidic): 1.82 min, m/z 514.1 [M+H]⁺

5-Amino-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.24 mmol) gave the titled compound (0.095 mmol) as an pale yellowsolid. UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 532.1 [M+H]⁺. UPLC-MS(ES⁺, Long acidic): 3.91 min, m/z 532.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.73 (t, J=6.6 Hz, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.50-7.39 (m, 5H), 7.16-7.14 (m, 1H), 7.04 (td, J=7.5, 1.0Hz, 1H), 6.34 (br s, 2H), 5.86 (br s, 1H), 4.54 (d, J=6.0 Hz, 2H),4.18-4.11 (m, 1H), 3.90 (s, 3H), 2.18-2.07 (m, 2H), 1.85-1.83 (m, 2H),1.73-1.63 (m, 4H).

Example 66:5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-(oxetan-3-ylideneamino)carbamate

Following general procedure E, 3-oxetanone (6.94 mmol) and tert-butylcarbazate (7.29 mmol) gave, after washing the crude with heptane, thetitled compound (4.51 mmol) as a white solid. H NMR (400 MHz, DMSO-d₆,δ): 10.25 (s, 1H), 5.19-5.15 (m, 4H), 1.43 (s, 9H)

tert-Butyl N-(oxetan-3-ylamino)carbamate

Following general procedure F, tert-butylN-(oxetan-3-ylideneamino)carbamate (4.40 mmol) gave after 2 days thetitled compound (3.84 mmol) as a colourless oil. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.38 (s, 1H), 4.96-4.94 (m, 1H), 4.51 (t, J=6.8 Hz, 2H),4.37 (t, J=6.2 Hz, 2H), 4.07-3.99 (m, 1H), 1.40 (s, 9H)

Oxetan-3-ylhydrazine hydrochloride

Following general procedure G, tert-butyl N-(oxetan-3-ylamino)carbamate(3.84 mmol) gave the titled compound (2.88 mmol) as a brown oil. ¹H NMR(400 MHz, DMSO-d₆, δ): 3.81-3.71 (m, 2H), 3.61-3.53 (m, 2H), 3.25-3.19(m, 1H)

5-Amino-3-(4-bromophenyl)-1-[1-(chloromethyl)-2-hydroxy-ethyl)pyrazole-4-carbonitrile

Following general procedure H at 85° C. for 2 h,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) andoxetan-3-ylhydrazine hydrochloride (0.46 mmol) gave the titled compound(0.21 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z357.1 [M+2]⁺

N-[[4-[5-Amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[1-(chloromethyl)-2-hydroxy-ethyl]pyrazole-4-carbonitrile(0.20 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.28 mmol) gavethe titled compound (0.13 mmol) as a white solid. UPLC-MS (ES+, Shortacidic): 1.50 min, m/z 440.2 [M]⁺

5-Amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.11 mmol) gave the titled compound (0.03 mmol) as a white solid.UPLC-MS (ES+, Short acidic): 1.33 min, m/z 458.2 [M]⁺. UPLC-MS (ES+,Long acidic): 2.98 min, m/z 458.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ):8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H), 7.51-7.41 (m, 5H),7.16 (d, J=8.0 Hz, 1H), 7.07-7.03 (m, 1H), 6.42 (s, 2H), 5.11 (t, J=5.4Hz, 1H), 4.59-4.52 (m, 3H), 4.02-3.93 (m, 2H), 3.91 (s, 3H), 3.78-3.67(m, 2H).

Example 67:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-methylthiazol-2-yl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(4-methylthiazol-2-yl)pyrazole-4-carbonitrile

Following general procedure H at 85° C. for 2 h,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol) and(4-methylthiazol-2-yl)hydrazine (0.91 mmol) gave, after purification,the titled compound (0.32 mmol) as a yellow solid. UPLC-MS (ES+, Shortacidic): 1.78 min, m/z 362.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(4-methylthiazol-2-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(4-methylthiazol-2-yl)pyrazole-4-carbonitrile(86 mg, 0.24 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (100 mg, 0.37 mmol)gave, after purification, the titled compound (0.08 mmol) as an orangesolid. UPLC-MS (ES+, Short acidic): 1.64 min, m/z 445.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-methylthiazol-2-yl)pyrazole-4carboxamide

Following general procedure M, N-[[4-[5-amino-4-cyano-1-(4-methylthiazol-2-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.05 mmol)gave, after purification, the titled compound (0.02 mmol) as a yellowsolid. UPLC-MS (ES+, Short acidic): 1.34 min, m/z 463.1 [M+H]⁺. UPLC-MS(ES+, Long acidic): 3.01 min, m/z 463.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.80-8.72 (m, 1H), 7.77 (dd, J=7.8, 1.9Hz, 1H), 7.52-7.47 (m, 1H), 7.44-7.35 (m, 4H), 7.30-7.29 (m, 1H),7.17-7.15 (m, 1H), 6.38-6.35 (m, 1H), 5.97 (s, 2H), 4.59 (d, J=6.9 Hz,2H), 3.91 (s, 3H), 2.14 (d, J=1.2 Hz, 3H)

Example 68:5-amino-1-(4,4-difluorocyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

(4,4-Difluorocyclohexyl)hydrazine hydrochloride

To a solution of 4,4-difluorocyclohexanol (5.40 mmol) in toluene (20 mL)was added triphenylphosphine (8.10 mmol) and di-tert-butylazodicarboxylate (6.48 mmol) and the reaction mixture was stirred for 16h at RT under nitrogen. The reaction mixture was concentrated. MeOH (30mL) and then a hydrogen chloride solution (4 M in 1,4-dioxane, 10.8 mL,43.19 mmol) was added and the mixture was stirred for 14 h at RT. Afterfiltration the filtrate was concentrated and addition of EtOAc gave thetitled compound (3.52 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆,δ): 3.11-3.05 (m, 1H), 2.11-1.78 (m, 6H), 1.63-1.53 (m, 2H)

5-Amino-3-(4-bromophenyl)-1-(4,4-difluorocyclohexyl)pyrazole-4-carbonitrile

Following general procedure H at 85° C. for 2 h,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (133 mg, 0.51mmol) and (4,4-difluorocyclohexyl)hydrazine hydrochloride (113 mg, 0.61mmol) gave, after purification, the titled compound (114 mg, 0.30 mmol,59% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 2.01 min, m/z383.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(4,4-difluorocyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(4,4-difluorocyclohexyl)pyrazole-4-carbonitrile(0.30 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.45 mmol) gave,after purification, the titled compound (0.26 mmol) as an orange solid.UPLC-MS (ES⁺, Short acidic): 1.79 min, m/z 466.1 [M+H]⁺

5-Amino-1-(4,4-difluorocyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure L,N-[[4-[5-amino-4-cyano-1-(4,4-difluorocyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(160 mg, 0.34 mmol) gave, after purification, the titled compound (0.11mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 484.2[M+H]⁺ UPLC-MS (ES⁺, Long acidic): 4.09 min, m/z 484.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7,1.8 Hz, 1H), 7.50-7.39 (m, 5H), 7.16-7.14 (m, 1H), 7.05-7.01 (m, 1H),6.36 (s, 2H), 4.54 (d, J=6.1 Hz, 2H), 4.34-4.26 (m, 1H), 3.89 (s, 3H),2.20-1.89 (m, 8H).

Example 69:5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-N-methyl-pyrazole-4-carboxamide

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylicacid

A mixture of ethyl5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylate(0.22 mmol), sodium hydroxide (5 M in water, 1 mL, 5.00 mmol) and MeOH(3 mL) in THF (5 mL) was stirred at 80° C. for 48 h. The mixture wasthen cooled and MeOH was removed under reduced pressure. The residue wasneutralized with hydrochloric acid (6 M) at 0° C. until a precipitatewas observed. The aqueous layer was then extracted and, afterconcentration, gave crude titled compound (0.20 mmol) as a light brownsolid. LC-MS (ES⁺, Short acidic): 4.87 min, m/z 435.2 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-N-methyl-pyrazole-4-carboxamide

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylicacid (30 mg, 0.07 mmol) was dissolved in DMF (3 mL) under nitrogen. HATU(34 mg, 0.09 mmol) and N,N-diisopropylethylamine (36 μL, 0.21 mmol) wereadded at RT. The mixture was stirred for 45 min. Then methylamine (2 Min THF, 104 μL, 0.21 mmol) was added and the mixture was stirred for 48h. After work-up and purification the titled compound (0.04 mmol) wasobtained as white solid. UPLC-MS (ES⁺, Short acidic): 1.80 min, m/z448.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 4.21 min, m/z 448.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆, δ): 8.72 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.7, 1.8Hz, 1H), 7.51-7.45 (m, 3H), 7.39-7.37 (m, 2H), 7.17-7.15 (m, 1H),7.07-7.03 (m, 1H), 6.18-6.11 (m, 1H), 6.11 (s, 2H), 4.64-4.57 (m, 1H),4.54 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 2.59 (d, J=4.7 Hz, 3H), 2.03-1.76(m, 6H), 1.64-1.56 (m, 2H).

Example 70:5-amino-1-[3-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(Isomer 1)

Lithium-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(Isomer 1)

A suspension of lithium hydroxide (9 mg, 0.39 mmol) in a solution ofethyl3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(isomer 1, 0.19 mmol) in THF (1.5 mL) and water (0.4 mL) was heated to60° C. for 16 h. The reaction was concentrated to give crude titledcompound (isomer 1, 0.19 mmol) that was used immediately in the nextstep. UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 492.1 [M+H]⁺

5-Amino-1-[3-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (Isomer 1)

Lithium-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(isomer 1, 95 mg, 0.19 mmol), in THF (2 mL), with a dimethylaminesolution (2 M in THF, 0.05 mL, 0.96 mmol) and a propylphosphonicanhydride solution (50 wt % in EtOAc, 0.34 mL, 0.57 mmol) was stirred atRT for 48 h. After work-up and purification the titled compound wasobtained (isomer 1, 0.03 mmol). UPLC-MS (ES⁺, Short acidic): 1.67 min,m/z 519.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.87 min, m/z 519.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.6,1.7 Hz, 1H), 7.51-7.38 (m, 5H), 7.16 (d, J=8.2 Hz, 1H), 7.08-7.01 (m,1H), 6.24 (br s, 2H), 4.70-4.60 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 3.90(s, 3H), 3.54-3.42 (m, 1H), 2.98 (s, 3H), 2.81 (s, 3H), 2.04-1.95 (m,1H), 1.89-1.51 (m, 7H).

Example 71:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazole-4-carboxamide

tert-Butyl N-(2-oxaspiro[3.5]nonan-7-ylideneamino)carbamate

Following general procedure E, 2-oxaspiro[3.5]nonan-7-one (120 mg, 0.86mmol) and tert-butyl carbazate (136 mg, 1.03 mmol) gave crude,tert-butyl N-(2-oxaspiro[3,5]nonan-7-ylideneamino)carbamate (0.86 mmol)as a white solid. ¹H NMR (400 MHz, DMSO-d₆, □): 9.58 (s, 1H), 4.33 (s,4H), 2.28-2.25 (m, 2H), 2.16-2.13 (m, 2H), 1.88-1.85 (m, 2H), 1.81-1.78(m, 2H), 1.43 (s, 9H).

5-Amino-3-(4-bromophenyl)-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazole-4-carbonitrile

tert-Butyl N-(2-oxaspiro[3.5]nonan-7-ylideneamino)carbamate (0.85 mmol)was dissolved in THF (10 mL) and a borane dimethyl sulfide complexsolution (2 M in THF, 0.73 mL, 1.45 mmol) was added. The reaction wasstirred at RT for 2 h. Volatiles were concentrated and the residue wasdissolved in DCM (5 mL), followed by addition of TFA (0.88 mL, 4.27mmol). The reaction mixture was stirred at 0° C. for 1 h and then at RTfor 1 h. Volatiles were removed under reduced pressure and the residuewas dissolved in EtOH (10 mL).2-[(4-Bromophenyl)-methoxy-methylene]propanedinitrile (0.65 mmol) andtriethylamine (3.23 mmol) were then added. The reaction mixture washeated to 80° C. for 3 h, then cooled to RT and concentrated.Purification gave the titled compound (0.30 mmol) as a yellow solid.UPLC-MS (ES⁺, Short acidic): 1.96 min, m/z 386.9 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazole-4-carbonitrile(0.22 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.31 mmol) gave,after purification, the titled compound (0.21 mmol) as a yellow solid.UPLC-MS (ES⁺, Short acidic): 1.78 min, 472.2 m/z [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.24 mmol) gave, after purification, the titled compound (0.06 mmol) asa beige solid. UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 490.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.89 min, m/z 490.2 [M+H]^(+. 1)H NMR (400MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.6, 1.8 Hz, 1H),7.51-7.46 (m, 1H), 7.44-7.39 (m, 4H), 7.18-7.13 (m, 1H), 7.06-7.02 (m,1H), 6.34 (s, 2H), 4.54 (d, J=6.7 Hz, 2H), 4.36 (s, 2H), 4.26 (s, 2H),4.11-4.00 (m, 1H), 3.90 (s, 3H), 2.21-2.11 (m, 2H), 1.79-1.62 (m, 4H),1.61-1.49 (m, 2H).

Example 72:1-cyclopentyl-5-(isopropylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

3-(4-Bromophenyl)-1-cyclopentyl-5-(isopropylamino)pyrazole-4-carbonitrile

The mixture of5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol), cesium carbonate (0.91 mmol) and 2-bromopropane (0.72 mmol) inDMF (10 mL) was heated to 50° C. for 16 h. After work-up andpurification the titled compound was afforded (0.13 mmol) as a brownsolid. UPLC-MS: (ES⁺, Short acidic): 2.45 min, m/z 375.0 [M+2]⁺

N-[[4-[4-Cyano-1-cyclopentyl-5-(isopropylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-1-cyclopentyl-5-(isopropylamino)pyrazole-4-carbonitrile(0.13 mol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.18 mmol) gave,after purification, the titled compound (0.12 mmol) as a light brownsolid.

UPLC-MS: (ES⁺, Short acidic): 2.18 min, m/z 458.2 [M+H]⁺

1-Cyclopentyl-5-(isopropylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[4-cyano-1-cyclopentyl-5-(isopropylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.12 mmol) gave, after purification, the titled compound (0.05 mmol) asa white solid. UPLC-MS: (ES⁺, Long acidic): 4.99 min, m/z 476.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆, □): 8.71 (t, J=6.4 Hz, 1H), 7.76 (dd, J=8.0,2.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.51-7.46 (m, 1H), 7.36 (d, J=8.4Hz, 2H), 7.17-7.15 (m, 1H), 7.07-7.01 (m, 1H), 5.29 (d, J=9.2 Hz, 1H),4.78-4.70 (m, 1H), 4.53 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 3.48-3.36 (m,1H), 2.06-1.79 (m, 6H), 1.69-1.59 (m, 2H), 1.11 (d, J=6.4 Hz, 6H).

Example 73:1-cyclopentyl-5-(ethylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

3-(4-Bromophenyl)-1-cyclopentyl-5-(ethylamino)pyrazole-4-carbonitrile

A mixture of5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol) and cesium carbonate (295 mg, 0.91 mmol) and iodoethane (0.36mmol) in DMF (5 mL) was stirred at RT for 14 h. After work-up andpurification the titled compound (0.15 mmol) was afforded as anoff-white solid. UPLC-MS: (ES⁺, Short acidic): 2.33 min, m/z 361.0[M+2]⁺

N-[[4-[4-Cyano-1-cyclopentyl-5-(ethylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-1-cyclopentyl-5-(ethylamino)pyrazole-4-carbonitrile(0.15 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.22 mmol) gave,after purification, the titled compound (0.14 mmol) as an off-whitesolid. UPLC-MS: (ES⁺, Short acidic): 2.11 min, m/z 444.2 [M+H]⁺

1-Cyclopentyl-5-(ethylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[4-cyano-1-cyclopentyl-5-(ethylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.14 mmol) gave, after purification, the titled compound (0.06 mmol) asa white solid. UPLC-MS (ES⁺, Long acidic): 4.84 min, m/z 462.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆, □): 8.71 (t, J=6.3 Hz, 1H), 7.75 (dd, J=7.6,1.8 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.51-7.46 (m, 1H), 7.36 (d, J=8.4Hz, 2H), 7.17-7.15 (m, 1H), 7.06-7.00 (m, 1H), 5.63 (t, J=6.4 Hz, 1H),4.74-4.68 (m, 1H), 4.53 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 3.18-3.11 (m,2H), 2.04-1.78 (m, 6H), 1.66-1.57 (m, 2H), 1.12 (t, J=7.1 Hz, 3H).

Example 74: Example 78:4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylicacid

4-[5-Amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylicacid

Lithium hydroxide (6.16 mmol) was added to a solution of ethyl4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate(0.62 mmol) in THF (3 mL) and water (1 mL). The reaction mixture wasstirred at 50° C. for 16 h and then cooled to RT. The reaction mixturewas acidified to ˜pH 2 with hydrochloric acid (1 M). Work-up andpurification afforded an inseparable mixture of cis and trans titledcompound (0.39 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.32min, m/z 492.3 [M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 3.67 min, m/z 492.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □ □ □ cis/trans mixture): 12.1 (br s, 1H), 8.73 (t, J=5.9 Hz,1H), 7.76 (dd, J=7.6, 1.6 Hz, 1H), 7.52-7.38 (m, 5H), 7.16 (d, J=8.3 Hz,1H), 7.08-7.01 (m, 1H), 6.40-6.25 (m, 2H), 4.55 (d, J=6.0 Hz, 2H),4.17-4.04 (m, 1H), 3.90 (s, 3H), 2.64-2.10 (m, 1H), 2.07-1.94 (m, 2H),1.93-1.39 (m, 6H).

Example 75:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[4-(methoxycarbamoyl)cyclohexyl]pyrazole-4-carboxamide

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[4(methoxycarbamoyl)cyclohexyl]pyrazole-4-carboxamide

A solution of propylphosphonic anhydride (50 wt % in EtOAc, 0.27 mmol),N,N-diisopropylethylamine (0.92 mmol), methoxyamine hydrochloride (0.22mmol) and4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylicacid (0.18 mmol) in THF (1 mL) was stirred at 80° C. for 16 h, cooled toRT. Work up and purification gave the title compound (0.03 mmol) as awhite solid. UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 521.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.58 min, m/z 521.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □, cis/trans mixture): 11.02 (s, 0.45H), 10.95 (s, 0.55H),8.78-8.70 (m, 1H), 7.79-7.73 (m, 1H), 7.52-7.38 (m, 5H), 7.16 (d, J=8.4Hz, 1H), 7.08-7.01 (m, 1H), 6.36 (s, 0.90H), 6.30 (s, 1.1 OH), 4.55 (d,J=6.0 Hz, 2H), 4.18-4.05 (m, 1H), 3.90 (s, 3H), 3.60-3.54 (m, 3H),2.33-2.24 (m, 0.45H), 2.12-1.92 (s, 2.55H), 1.92-1.49 (m, 6H).

Example 76:5-amino-1-cyclopentyl-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

(4-Bromo-2-fluoro-phenyl)methanamine

4-Bromo-2-fluorobenzonitrile (5.00 mmol) in THF (30 mL) was cooled to 0°C. A borane tetrahydrofuran complex solution (1 M in THF, 15.0 mL) wasadded dropwise. The solution was stirred at 0° C. for 20 min beforebeing brought up to RT and stirred for 16 h. MeOH was added dropwise (30mL) and the solution was concentrated under reduced pressure. Theresidue was partitioned between an aqueous solution of NaOH (1 M) andEtOAc. The organic layer was worked up to give the titled compound (5.00mmol) as a yellow oil. ¹H NMR (400 MHz, CDCl₃, □): 7.42-7.27 (m, 1H),7.25-7.16 (m, 2H), 3.65 (t, J=6.6 Hz, 2H).

N-[4-Bromo-2-fluoro-phenyl)methyl]-5-fluoro-2-methoxy-benzamide

A solution of (4-bromo-2-fluoro-phenyl)methanamine (5.00 mmol) in THF (8mL) was added dropwise to a mixture of 5-fluoro-2-methoxybenzoic acid(1.03 g, 6.04 mmol), N,N-diisopropylethylamine (5.22 mL, 30.0 mmol) anda propylphosphonic anhydride solution (50 wt % in EtOAc, 4.46 mL, 7.50mmol) in THF (17 mL). The reaction was heated at 80° C. for 4 h. Work-upand concentration afforded the title compound (3.18 mmol). UPLC-MS (ES⁺,Short acidic): 1.98 min, m/z 357.9 [M+2]⁺

5-Fluoro-N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure R,N-[(4-bromo-2-fluoro-phenyl)methyl]-5-fluoro-2-methoxy-benzamide (3.34mmol) gave, after purification, the titled compound (3.30 mmol). UPLC-MS(ES⁺, Short acidic): 2.14 min, m/z 404.0 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure D,5-fluoro-N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide(1.65 mmol) and 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1.34 mmol)gave, after purification, titled compound (0.78 mmol). UPLC-MS (ES⁺,Short acidic): 1.67 min, m/z 384.0 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Cesium carbonate (1.64 mmol),N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(1.27 mmol) and bromocyclopentane (1.39 mmol) in DMF (10 mL) was heatedto 80° C. for 18 h. Work-up and purification gave the titled compound(0.21 mmol). UPLC-MS (ES⁺, Short acidic): 2.04 min, m/z 452.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.11 mmol) afforded, after purification, titled compound (0.07 mmol).UPLC-MS (ES⁺, Short acidic): 1.93 min, m/z 470.1 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 5.12 min, m/z 470.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ):8.81 (t, J=5.9 Hz, 1H), 7.51 (dd, J=9.2, 3.3 Hz, 1H), 7.46-7.40 (m, 1H),7.38-7.25 (m, 3H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 6.25 (s, 2H), 4.67-4.58(m, 1H), 4.56 (d, J=5.9 Hz, 2H), 3.90 (s, 3H), 2.03-1.84 (m, 4H),1.84-1.74 (m, 2H), 1.65-1.54 (m, 2H).

Example 77:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyltetrahydrofuran-3-yl]pyrazole-4-carboxamide(Isomer 1)

tert-Butyl N-[(2-methyltetrahydrofuran-3-ylidene)amino]carbamate

tert-Butyl carbazate (11.99 mmol) and 2-methyltetrahydro-3-furanone(9.99 mmol) in EtOH (25 mL) was heated to reflux for 16 h, cooled andconcentrated under reduced pressure. The residue was taken up with DCM,washed successively with water and a saturated solution of NaHCO₃, driedover sodium sulfate and concentrated under reduced pressure to affordthe titled compound (9.99 mmol) as a white solid. ¹H NMR (400 MHz,CDCl₃, δ): 7.22 (s, 1H), 4.39-4.31 (m, 1H), 4.27-4.19 (m, 1H), 3.97-3.88(m, 1H), 2.53-2.46 (m, 2H), 1.54 (s, 9H), 1.44 (d, J=6.4 Hz, 3H).

(2-Methyltetrahydrofuran-3-yl)hydrazine

General procedures T and U, tert-butylN-[(2-methyltetrahydrofuran-3-ylidene)amino]carbamate (9.99 mmol) gave,after purification by SPE SCX cartridge eluting with 1 M solution of NH₃in MeOH, (2-methyltetrahydrofuran-3-yl)hydrazine (9.33 mmol). ¹H NMR(400 MHz, CDCl₃, δ): 4.03-3.66 (m, 3H), 3.31-3.24 (m, 1H), 2.18-2.05 (m,1H), 1.95-1.85 (m, 1H), 1.30-1.22 (m, 3H).

5-Amino-3-(4-bromophenyl)-1-(2-methyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.90 mmol) and(2-methyltetrahydrofuran-3-yl)hydrazine (2.28 mmol) gave, afterpurification, the titled compound as a mixture of inseparablediastereoisomers (600 mg, 1.73 mmol, 91% yield).

UPLC-MS (ES⁺, Short acidic, mixture of disastereoisomers): 2.02 min, m/z349.0 [M+2]⁺ and 2.07 min, m/z 349.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[2-methyltetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2-methyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile(0.86 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.21 mmol) gave,after purification, the titled compound (isomer 1, 0.17 mmol) and(isomer 2, 0.32 mmol). UPLC-MS (ES⁺, Short acidic, isomer 1): 1.98 min,m/z 432.1 [M+H]⁺. UPLC-MS (ES⁺, Short acidic, isomer 2): 1.96 min, m/z432.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyltetrahydrofuran-3-yl]pyrazole-4-carboxamide(Isomer 1)

Following general procedure L,N-[[4-[5-amino-4-cyano-1-[2-methyltetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 1, 0.17 mmol) gave, after purification, the titled compound(isomer 1, 0.09 mmol). UPLC-MS (ES⁺, Short acidic): 2.03 min, m/z 450.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 4.49 min, m/z 450.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.3 Hz, 1H), 7.75 (dd, J=7.6, 1.7 Hz,1H), 7.51-7.38 (m, 5H), 7.15 (d, J=8.5 Hz, 1H), 7.08-7.00 (m, 1H), 6.43(br s, 2H), 4.55 (d, J=5.9 Hz, 2H), 4.51-4.44 (m, 1H), 4.08-4.02 (m,1H), 3.95-3.90 (m, 2H), 3.90 (s, 3H), 2.38-2.18 (m, 2H), 1.21 (d, J=6.2Hz, 3H).

Example 78:5-chloro-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

3-(4-Bromophenyl)-1H-pyrazol-5-ol

A solution of ethyl 3-(4-bromophenyl)-3-oxopropanoate (12.2 mmol) inEtOH (20 mL) and hydrazine hydrate solution (55-60% in water, 12.2 mmol)was stirred for 40 min at RT. The reaction mixture was then heated atreflux for 1 h, then cooled to RT and concentrated under reducedpressure to give the titled compound crude (12.2 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 240.6 [M+2]⁺

3-(4-Bromophenyl)-5-chloro-1H-pyrazole-4-carbaldehyde

To phosphorus oxychloride (29.3 mmol) was added slowly under nitrogen at0° C. anhydrous DMF (1.0 mL). The reaction mixture was then warmed to RTand stirred for 5 min then 3-(4-bromophenyl)-1H-pyrazol-5-ol (4.18 mmol)was added to the reaction mixture at 0° C. After the addition, thereaction mixture was heated at 85° C. for 24 h. The reaction mixture wascooled to RT and quenched with a saturated solution of potassiumcarbonate (20 mL), and extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. Purification gave the titled compound (2.31mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z286.8 [M+H]⁺

3-(4-Bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carbaldehyde

General procedure N,3-(4-bromophenyl)-5-chloro-1H-pyrazole-4-carbaldehyde (2.31 mmol),cesium carbonate (4.62 mmol) and bromocyclopentane (3.47 mmol) gave,after purification, the titled compound (1.35 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 2.49 min, m/z 354.9 [M+H]⁺

3-(4-Bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carboxylic acid

To a suspension of3-(4-bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carbaldehyde (0.46mmol) in water (5 mL) was added potassium permanganate (0.91 mmol) atRT. The reaction mixture was heated at 100° C. for 18 h and then cooledto RT, filtered through Celite® and washed with water and EtOAc. The twolayers were separated and the aqueous layer was acidified to pH 1 with a1 M solution of HCl. The aqueous layer was then extracted with EtOAc(3×20 mL). The combined organic layers were dried over sodium sulfate,and concentrated under reduced pressure to give a mixture the titledcompound and 3-(4-bromophenyl)-5-chloro-1H-pyrazole-4-carboxylic acid(1:2 ratio) (0.86 mmol) which was used as such in the next step. UPLC-MS(ES⁺, Short acidic): 2.31 min, m/z 370.9 [M+H]⁺

3-(4-Bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carboxamide

A mixture 3-(4-bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carboxylicacid and 3-(4-bromophenyl)-5-chloro-1H-pyrazole-4-carboxylic acid (1:2ratio) (0.86 mmol) in thionyl chloride (4.30 mmol) was heated at 80° C.for 1 h. The excess of thionyl chloride was removed under reducedpressure to afford a brown oil which was dissolved in anhydrous DCM (1.9mL) under nitrogen at 0° C. with an ice bath. Ammonium hydroxide (30 wt% in water, 8.58 mmol) was added dropwise to the cooled reaction mixtureand then it was stirred to RT for 16 h. The reaction mixture was thendiluted in DCM and washed with water. The aqueous layer was extractedwith DCM (×3) and the combined organic layers were dried over sodiumsulfate, filtered off and concentrated under reduced pressure.Purification gave the titled compound (0.10 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 2.24 min, m/z 369.9 [M+H]⁺

5-Chloro-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure K,3-(4-bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carboxamide (0.10mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide(29 mg, 0.11 mmol) gave, after purification, the titled compound (0.03mmol) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 2.23 min, m/z 453.0 [M]⁺. UPLC-MS (ES⁺,Long acidic): 6.07 min, m/z 453.1 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ):8.71 (t, J=6.0 Hz, 1H), 7.74 (dd, J=7.6, 1.8 Hz, 1H), 7.67 (br s, 1H),7.63 (d, J=8.5 Hz, 2H), 7.53 (br s, 1H), 7.50-7.44 (m, 1H), 7.36 (d,J=8.4 Hz, 2H), 7.14 (d, J=7.8 Hz, 1H), 7.06-7.00 (m, 1H), 4.90-4.83 (m,1H), 4.51 (d, J=6.2 Hz, 2H), 3.89 (s, 3H), 2.13-2.05 (m, 2H), 2.03-1.94(m, 2H), 1.91-1.81 (m, 2H), 1.72-1.64 (m, 2H).

Example 79:5-amino-1-cyclopentyl-3-[4-[1-[(2-methoxybenzoyl)amino]ethyl]phenyl]pyrazole-4-carboxamide

N-[1-(4-Bromophenyl)ethyl]-2-methoxy-benzamide

A solution of 4-bromo-α-methylbenzylamine (6.57 mmol) andN,N-diisopropylethylamine (9.85 mmol) in anhydous THF (30 mL) and2-methoxybenzoyl chloride (7.22 mmol) at 0° C. was then allowed toreturn to RT and stirred for 15 h. The mixture was quenched with asaturated solution of ammonium chloride (40 mL), extracted with EtOAc(3×20 mL). The combined organic extracts were washed with water (2×30mL), a saturated solution of brine (30 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. Further purificationgave the titled compound (6.19 mmol) as a white solid. UPLC-MS (ES⁺,Short acidic): 1.96 min, m/z 336.1[M+2]⁺

2-Methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]benzamide

General procedure J, N-[1-(4-bromophenyl)ethyl]-2-methoxy-benzamide(0.90 mmol) gave, after purification, the titled compound (0.87 mmol) asan orange oil. UPLC-MS (ES⁺, Short acidic): 2.12 min, m/z 382.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[1-[(2-methoxybenzoyl)amino]ethyl]phenyl]pyrazole-4-carboxamide

General procedure D,5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (0.26 mmol) and2-methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]benzamide(0.26 mmol) gave, after purification, the titled compound (0.03 mmol) asa light brown solid.

UPLC-MS (ES⁺, Short acidic): 2.47 min, m/z 448.2 [M+H]⁺. UPLC-MS (ES⁺,Long acidic): 5.82 min, m/z 448.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ):8.52 (d, J=8.0 Hz, 1H), 7.63 (dd, J=7.7, 1.8 Hz, 1H), 7.50-7.42 (m, 5H),7.14 (d, J=7.8 Hz, 1H), 7.05-6.98 (m, 1H), 6.30 (br s, 2H), 5.22-5.12(m, 1H), 4.65-4.55 (m, 1H), 3.90 (s, 3H), 2.02-1.84 (m, 4H), 1.84-1.70(m, 2H), 1.64-1.51 (m, 2H), 1.48 (d, J=7.0 Hz, 3H)

Example 80:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

A modified general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.49 mmol) andtetrahydropyran-3-ylhydrazine hydrochloride (0.49 mmol) afforded, afterpurification, the titled compound (0.24 mmol) as a beige solid. UPLC-MS(ES⁺, Short acidic): 2.17 min, m/z 346.9 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.24 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.27 mmol)afforded, after purification, the titled compound (0.24 mmol) as ayellow oil. UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 432.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.21 mmol) afforded, after purification, the titled compound (0.04mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.91 min, m/z450.2 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 5.07 min, m/z 450.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.7, 1.7Hz, 1H), 7.52-7.38 (m, 5H), 7.16 (d, J=8.2 Hz, 1H), 7.05 (m, 1H), 6.42(s, 2H), 4.55 (d, J=6.1 Hz, 2H), 4.30-4.21 (m, 1H), 3.93-3.81 (m, 5H),3.59-3.49 (m, 1H), 3.37-3.27 (m, 1H), 2.05-1.96 (m, 2H), 1.80-1.64 (m,2H).

Example 81:5-amino-1-(2,3-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2,3-difluorophenyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) and(2,3-difluorophenyl)hydrazine (0.46 mmol) afforded, after purification,the titled compound (0.29 mmol) as an orange solid. UPLC-MS (ES⁺, Shortacidic): 2.08 min, m/z 376.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,3-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,3-difluorophenyl)pyrazole-4-carbonitrile(0.29 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.41 mmol) gave,after purification, the titled compound (0.14 mmol) as a grey solid.UPLC-MS (ES⁺, Short acidic): 1.89 min, m/z 460.1 [M+H]⁺

5-Amino-1-(2,3-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2,3-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.14 mmol) afforded, after purification, the titled compound (0.03mmol, 22% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.77min, m/z 478.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 4.21 min, m/z 478.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.0 Hz, 1H), 7.77 (dd,J=7.6, 1.6 Hz, 1H), 7.66-7.34 (m, 8H), 7.16 (d, J=8.4 Hz, 1H), 7.06-7.02(m, 1H), 6.58 (s, 2H), 4.56 (d, J=6.4 Hz, 2H), 3.90 (s, 3H).

Example 82:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)pyrazole-4-carboxamide

tert-ButylN-[(2,2,5,5-tetramethyltetrahydrofuran-3-ylidene)amino]carbamate

General procedure E, dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (1.63mmol) and tert-butyl carbazate (258 mg, 1.95 mmol) gave the titledcompound crude (1.62 mmol) as a white solid. ¹H NMR (400 MHz, CDCl₃, □):7.11 (s, 1H), 2.47 (s, 2H), 1.51 (s, 9H), 1.42 (s, 6H), 1.34 (s, 6H).

5-Amino-3-(4-bromophenyl)-1-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile

tert-ButylN-[(2,2,5,5-tetramethyltetrahydrofuran-3-ylidene)amino]carbamate (1.62mmol) was dissolved in THF (10 mL) and a borane dimethyl sulfide complexsolution (2 M in THF, 2.75 mmol) was added. The reaction mixture wasstirred at RT for 2 h until TLC showed complete consumption of thestarting material. Volatiles were removed under reduced pressure. Theresidue was taken up with DCM (5 mL) and TFA (8.10 mmol) was added andthe mixture was stirred at RT for 1 h. The reaction mixture was thenconcentrated under reduced pressure. The residue was dissolved in EtOH(10 mL) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.65mmol) and triethylamine (3.23 mmol) were added. The reaction mixture washeated to 80° C. for 24 h. The solvent was removed under reducedpressure and the residue was purified to give the titled compound (0.23mmol) as a solid.

UPLC-MS (ES⁺, Short acidic): 2.33 min, m/z 389.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile(0.23 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.32 mmol) gave,after purification, the titled compound (0.19 mmol) as a yellow solid.UPLC-MS: (ES⁺, Short acidic): 2.09 min, m/z 474.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.19 mmol) gave, after purification, the titled compound (0.10 mmol) asa solid. UPLC-MS (ES⁺, Short acidic): 2.02 min, m/z 492.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 4.79 min, m/z 492.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.73 (t, J=6.2 Hz, 1H), 7.75 (dd, J=7.5, 1.7 Hz, 1H),7.49-7.40 (m, 5H), 7.15 (d, J=8.6 Hz, 1H), 7.05-7.01 (m, 1H), 6.43 (s,2H), 4.92-4.87 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 2.81-2.73(m, 1H), 2.13-2.09 (m, 1H), 1.30 (s, 6H), 1.26 (s, 3H), 0.90 (s, 3H).

Example 83a:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

[(3S)-Tetrahydrofuran-3-yl]hydrazine hydrochloride

A solution of (3S)-tetrahydrofuran-3-ol (11.35 mmol) in toluene (20 mL),triphenylphosphine (17.0 mmol), and di-tert-butylazodicarboxylate (13.6mmol) was stirred under nitrogen at RT for 48 h, then concentrated underreduced pressure and the residue redissolved in MeOH (50 mL). A hydrogenchloride solution (4 M in dioxane, 90.79 mmol) was added and thereaction mixture stirred at RT for 16 h. The reaction mixture wasfiltered and the filtrate concentrated under reduced pressure. Theresidue was recrystallized in EtOAc and MeOH to give the titled compound(7.32 mmol) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆, □): 3.81-3.72(m, 3H), 3.69-3.62 (m, 2H), 2.07-1.98 (m, 1H), 1.96-1.88 (m, 1H).

N-[[4-[5-Amino-4-cyano-1-[(3M-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carbonitrile(0.39 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.59 mmol) gave,after purification, the titled compound (0.35 mmol) as a light brownsolid. UPLC-MS (ES⁺, Short acidic): 1.94 min, m/z 418.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-[(3S)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.18 mmol) gave, after purification, the titled compound (0.08 mmol) asa pale yellow solid. UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 436.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.96 min, m/z 436.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7, 1.7 Hz,1H), 7.50-7.40 (m, 5H), 7.15 (d, J=7.7 Hz, 1H), 7.06-7.02 (m, 1H), 6.39(s, 2H), 4.93-4.90 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 4.00-3.92 (m, 2H),3.90 (s, 3H), 3.83-3.79 (m, 2H), 2.30-2.20 (m, 2H).

Example 83b:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

[(3R)-Tetrahydrofuran-3-yl]hydrazine hydrochloride

A solution of (S)-(−)-3-hydroxytetrahydrofuran (11.4 mmol) in toluene(20 mL), triphenylphosphine (17.0 mmol) anddi-tert-butylazodicarboxylate (13.6 mmol) at 0° C. was stirred for 48 hat RT under nitrogen. Volatiles were removed under reduced pressure.MeOH (50 mL) and a hydrogen chloride solution (4 M in dioxane, 90.8mmol) were then added. The reaction mixture was stirred for 16 h at RT,and then filtered. The filtrate was concentrated under reduced pressure.The residue was triturated with EtOAc to give the titled compound (5.4mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, δ): 3.82-3.62 (m, 5H),2.08-1.99 (m, 1H), 1.94-1.87 (m, 1H)

N-[[4-[5-Amino-4-cyano-1-[(3R)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carbonitrile(0.27 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.41 mmol) gave,after purification, the titled compound (0.27 mmol) as an beige solid.UPLC-MS (ES+, Short acidic): 1.50 min, m/z 418.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-[(3R)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.30 mmol) gave, after purification, the titled compound (0.11 mmol) asa white solid. LC-MS (ES+, Short acidic): 3.94 min, m/z 436.1 [M+H]⁺.UPLC-MS (ES+, Long acidic): 2.96 min, m/z 436.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7, 1.8 Hz, 1H),7.50-7.39 (m, 5H), 7.16-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.39 (s, 2H),4.96-4.90 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 4.01-3.92 (m, 2H), 3.90 (s,3H), 3.82-3.77 (m, 2H), 2.28-2.23 (m, 2H).

Example 84:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyltetrahydrofuran-3-yl]pyrazole-4-carboxamide(Isomer 2)

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyltetrahydrofuran-3-yl]pyrazole-4-carboxamide(Isomer 2)

General procedure M,N-[[4-[5-amino-4-cyano-1-[2-methyltetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 2, 0.32 mmol) gave, after purification, the titled compound(isomer 2, 0.07 mmol). UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 450.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.02 min, m/z 450.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.7, 1.7 Hz,1H), 7.51-7.39 (m, 5H), 7.16 (d, J=8.2 Hz, 1H), 7.06-7.02 (m, 1H), 6.39(br s, 2H), 4.88-4.80 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 4.14-4.05 (m,1H), 4.05-3.96 (m, 1H), 3.90 (s, 3H), 3.64 (q, J=8.1 Hz, 1H), 2.54-2.44(m, 1H), 2.41-2.31 (m, 1H), 0.83 (d, J=6.1 Hz, 3H).

Example 85:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-methyltetrahydropyran-4-yl)pyrazole-4-carboxamide

tert-Butyl N-[(2-methyltetrahydropyran-4-ylidene)amino]carbamate

General procedure E, 2-methyldihydro-2H-pyran-4(3H)-one (2.03 mmol) andtert-butyl carbazate (2.23 mmol) gave the titled compound crude (2.04mmol) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃, □): 7.56 (s, 1H),4.17-4.12 (m, 1H), 3.65-3.59 (m, 1H), 3.53-3.49 (m, 1H), 2.62-2.55 (m,1H), 2.52-2.47 (m, 1H), 2.24-2.16 (m, 1H), 1.90-1.84 (m, 1H), 1.54 (s,9H), 1.33-1.27 (m, 3H).

5-Amino-3-(4-bromophenyl)-1-(2-methyltetrahydropyran-4-yl)pyrazole-4-carbonitrile

tert-Butyl N-[(2-methyltetrahydropyran-4-ylidene)amino]carbamate (2.03mmol) in THF (10 mL) and a borane dimethyl sulfide complex solution (2 Min THF, 3.45 mmol) was stirred at RT for 2 h until TLC showed completeconsumption of the starting material. Volatiles were removed underreduced pressure. The residue was dissolved in DCM (10 mL) and TFA (10.1mmol) was added. The reaction mixture was stirred at RT for 1 h and thenconcentrated under reduced pressure. The residue was dissolved in EtOH(10 mL). 2-[(4-Bromophenyl)-methoxy-methylene]propanedinitrile (0.95mmol) and triethylamine (4.75 mmol) were added. The reaction mixture washeated to 80° C. for 24 h, cooled and concentrated under reducedpressure. Further purification gave the titled compound (0.25 mmolmixture of diastereoisomers) as a beige solid. UPLC-MS: (ES⁺, Shortacidic): 1.85 min, m/z 362.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2-methyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2-methyltetrahydropyran-4-yl)pyrazole-4-carbonitrile(0.23 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.33 mmol) gave,after purification, the titled compound (0.22 mmol) as a yellow solid.UPLC-MS: (ES⁺, Short acidic): 1.58 min, m/z 446.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-methyltetrahydropyran-4-yl)pyrazole-4-carboxamide

Procedure L,N-[[4-[5-amino-4-cyano-1-(2-methyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(100 mg, 0.22 mmol) gave, after purification, the titled compound (0.04mmol) as a white solid. UPLC-MS: (ES⁺, Short acidic): 1.40 and 1.43 min,m/z 464.1 [M+H]⁺. UPLC-MS: (ES⁺, Long acidic): 3.12 and 3.20 min, m/z464.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ, mixture of diastereoisomers):8.74 (t, J=6.3 Hz, 1H), 7.76 (dd, J=7.6, 1.7 Hz, 1H), 7.51-7.41 (m, 5H),7.16 (d, J=8.2 Hz, 1H), 7.07-7.03 (m, 1H), 6.38 (s, 2H), 4.55 (d, J=6.0Hz, 2H), 4.42-4.34 (m, 1H), 3.98-3.95 (m, 1H), 3.91 (s, 3H), 3.55-3.44(m, 2H), 1.92-1.82 (m, 2H), 1.77-1.62 (m, 2H), 1.16-1.12 (m, 3H).

Example 86:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-methyltetrahydropyran-4-yl)pyrazole-4-carboxamide

tert-Butyl N-[(3-methyltetrahydropyran-4-ylidene)amino]carbamate

General procedure E, 3-methyldihydro-2H-pyran-4(3H)-one (1.75 mmol) andtert-butyl carbazate (1.93 mmol) gave the titled compound crude (1.69mmol) as a white solid. ¹H NMR (400 MHz, CDCl₃, □): 7.52 (s, 1H),3.94-3.90 (m, 1H), 3.89-3.84 (m, 1H), 3.75-3.69 (m, 1H), 3.49-3.44 (m,1H), 2.69-2.61 (m, 1H), 2.52-2.46 (m 1H), 2.31-2.23 (m, 1H), 1.53 (s,9H), 1.20 (d, J=6.9 Hz, 3H).

5-Amino-3-(4-bromophenyl)-1-(3-methyltetrahydropyran-4-yl)pyrazole-4-carbonitrile

tert-Butyl N-[(3-methyltetrahydropyran-4-ylidene)amino]carbamate (1.69mmol) dissolved in THF (10 mL) and a borane dimethyl sulfide complexsolution (2 M in THF, 2.86 mmol) was stirred at RT for 2 h until TLCshowed complete consumption of the starting material. Solvent wasremoved under reduced pressure. The residue was dissolved in DCM (7 mL)and TFA (8.43 mmol) was added. The reaction mixture was stirred at RTfor 2 h and then concentrated under reduced pressure. The residue wasdissolved in EtOH (10 mL) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.37 mmol) andtriethylamine (6.84 mmol) were added. The reaction mixture was heated to80° C. for 24 h, cooled and concentrated under reduced pressure. Furtherpurification gave the titled compound (1.15 mmol) as a white solid.UPLC-MS: (ES⁺, Short acidic): 1.83 min and 1.86 min, m/z 362.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3-methyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3-methyltetrahydropyran-4-yl)pyrazole-4-carbonitrile(0.48 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.71 mmol) gave,after purification, the titled compound (0.48 mmol) as a white solid.UPLC-MS: (ES⁺, Short acidic): 1.59 min and 1.61 min, m/z 446.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-methyltetrahydropyran-4-yl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-methyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.14 mmol) gave, after purification, the titled compound (0.09 mmol) asa solid. UPLC-MS: (ES⁺, Short acidic): 1.36 min, 1.38 min, m/z 464.1[M+H]⁺. UPLC-MS: (ES⁺, Short acidic): 3.06 min, 3.13 min, m/z 464.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □ □ □ mixture of diastereoisomers):8.74 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.6, 2.0 Hz, 1H), 7.51-7.41 (m, 5H),7.15 (d, J=8.2 Hz, 1H), 7.07-7.03 (m, 1H), 6.40 (s, 2H), 4.55 (d, J=6.1Hz, 2H), 4.52-4.47 (m, 1H), 4.06-4.01 (m, 1H), 3.91 (s, 3H), 3.72 (dd,J=11.3, 3.5 Hz, 1H), 3.58 (dd, J=11.2, 2.6 Hz, 1H), 3.51-3.41 (m, 1H),2.36-2.29 (m, 1H), 2.17-2.14 (m, 1H), 1.71-1.66 (m, 1H), 0.80 (d, J=7.0Hz, 3H).

Example 87:1-cyclobutyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)pyrazole-4-carboxamide

3-(4-Bromophenyl)-1-cyclobutyl-5-(methylamino)pyrazole-4-carbonitrile

5-Amino-3-(4-bromophenyl)-1-cyclobutyl-pyrazole-4-carbonitrile (0.28mmol) dissolved in MeOH (2.8 mL), paraformaldehyde (0.85 mmol) andsodium methoxide (25 wt % in MeOH, 1.70 mmol) were heated at 70° C. for1 h and then cooled to RT. Sodium borohydride (2.84 mmol) was added andthe reaction mixture was stirred at RT for another 16 h. The reactionmixture was then carefully quenched with water. The aqueous layer wasthen extracted with DCM (×3). The combined organic layers were filteredover a hydrophobic frit and concentrated under reduced pressure. Furtherpurification afforded the titled compound (0.23 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 2.25 min, m/z 331.0 [M]⁺

N-[[4-[4-Cyano-1-cyclobutyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-1-cyclobutyl-5-(methylamino)pyrazole-4-carbonitrile(0.23 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.25 mmol) gave,after purification, the titled compound (0.21 mmol) as a white powder.UPLC-MS (ES⁺, Short acidic): 2.11 min, m/z 416.1 [M+H]⁺

1-Cyclobutyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)pyrazole-4-carboxamide

General procedure L,N-[[4-[4-cyano-1-cyclobutyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.17 mmol) gave, after purification, the titled compound (0.09 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 434.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.56 min, m/z 434.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.72 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.7, 1.7 Hz, 1H), 7.54(d, J=8.2 Hz, 2H), 7.51-7.44 (m, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.15 (d,J=8.2 Hz, 1H), 7.07 (br s, 1H), 7.07-7.00 (m, 1H), 6.36 (br s, 1H), 5.92(q, J=5.6 Hz, 1H), 4.84-4.80 (m, 1H), 4.53 (d, J=6.0 Hz, 2H), 3.90 (s,3H), 2.81 (d, J=5.4 Hz, 3H), 2.64-2.44 (m, 2H), 2.38-2.24 (m, 2H),1.83-1.70 (m, 2H).

Example 88:5-amino-1-cyclopentyl-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.23mmol) and5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.17mmol) gave, after purification, the titled compound (0.17 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 434.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.17 mmol) afforded, after purification, the titled compound (0.10mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 452.1[M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 3.62 min, m/z 452.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.83 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2, 3.3 Hz, 1H), 7.44(d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.37-7.30 (m, 1H), 7.18 (dd,J=9.2, 4.3 Hz, 1H), 6.31 (s, 2H), 4.65-4.66 (m, 1H), 4.54 (d, J=6.1 Hz,2H), 3.89 (s, 3H), 2.02-1.84 (m, 4H), 1.82-1.73 (m, 2H), 1.63-1.52 (m,2H)

Example 89:5-amino-1-(3,3-dimethyltetrahydropyran-4-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(3,3-dimethyl tetrahydropyran-4-ylidene)amino]carbamate

General procedure E, 3,3-dimethyldihydro-2H-pyran-4(3H)-one (1.72 mmol)and tert-butyl carbazate (1.89 mmol) gave the titled compound (1.70mmol) as a white solid. ¹H NMR (400 MHz, CDCl₃, □): 7.46 (s, 1H), 3.77(t, J=6.1 Hz, 2H), 3.46 (s, 2H), 2.36 (t, J=6.0 Hz, 2H), 1.50 (s, 9H),1.19 (s, 6H).

[(3,3-Dimethyltetrahydropyran-4-yl)amino]ammonium;2,2,2-trifluoroacetate

tert-Butyl N-[(3,3-dimethyltetrahydropyran-4-ylidene)amino]carbamate(1.69 mol) dissolved in THF (10 mL) and a borane dimethyl sulfidecomplex solution (2 M in THF, 2.88 mmol) was stirred at RT for 2 h untilTLC showed complete consumption of the starting material. Volatiles wereremoved under reduced pressure. The residue was dissolved in DCM (7 mL)and TFA (8.46 mmol) was added. The reaction mixture was stirred at RTfor 2 h. The volatiles were then removed under reduced pressure toafford the titled compound crude (1.70 mmol).

1H NMR (400 MHz, DMSO-d₆, □): 3.93-3.89 (m, 1H), 3.33 (d, J=11.2 Hz,1H), 3.29-3.22 (m, 1H), 3.01 (d, J=11.5 Hz, 1H), 2.71-2.67 (m, 1H),1.88-1.84 (m, 1H), 1.53-1.43 (m, 1H), 0.88 (d, J=11.2 Hz, 6H).

(5-Amino-3-(4-bromophenyl)-1-(3,3-dimethyltetrahydropyran-4-yl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol) and[(3,3-dimethyltetrahydropyran-4-yl)amino]ammonium;2,2,2-trifluoroacetate (0.91 mmol) gave, after purification, the titledcompound (0.72 mmol) as a white solid. UPLC-MS: (ES⁺, Short acidic):1.91 min, m/z 376.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3,3-dimethyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3,3-dimethyltetrahydropyran-4-yl)pyrazole-4-carbonitrile(0.27 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.40 mmol) gave,after purification, the titled compound (0.21 mmol) as a yellow solid.UPLC-MS: (ES⁺, Short acidic): 1.64 min, m/z 460.1 [M+H]⁺

5-Amino-1-(3,3-dimethyltetrahydropyran-4-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(3,3-dimethyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.21 mmol) gave, after purification, the titled compound (0.13 mmol) asa solid. UPLC-MS: (ES⁺, Short acidic): 1.44 min, m/z 478.1 [M+H]⁺.UPLC-MS: (ES⁺, Long acidic): 3.30 min, m/z 478.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.6, 1.7 Hz, 1H),7.50-7.40 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.05-7.02 (m, 1H), 6.40 (s,2H), 4.54 (d, J=6.5 Hz, 2H), 4.21 (dd, J=11.1, 4.0 Hz, 1H), 4.04-3.90(m, 4H), 3.51-3.39 (m, 2H), 3.20 (d, J=11.1 Hz, 1H), 2.39-2.29 (m, 1H),1.58-1.54 (m, 1H), 1.01 (s, 3H), 0.81 (s, 3H).

Example 90:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazole-4-carboxamide

tert-ButylN-[(2,2,6,6-tetramethyltetrahydropyran-4-ylidene)amino]carbamate

General procedure E, 2,2,6,6-tetramethyloxan-4-one (1.60 mmol) andtert-butyl carbazate (2.44 mmol) gave, after purification, the titledcompound (1.44 mmol) as an off-white solid. ¹H NMR (400 MHz, CDCl₃, □):7.47 (s, 1H), 2.52 (s, 2H), 2.25 (s, 2H), 1.51 (s, 9H), 1.29 (s, 6H),1.23 (s, 6H).

5-Amino-3-(4-bromophenyl)-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazole-4-carbonitrile

tert-ButylN-[(2,2,6,6-tetramethyltetrahydropyran-4-ylidene)amino]carbamate (1.47mmol) was dissolved in THF (15 mL) and a borane dimethyl sulfide complexsolution (2 M in THF, 4.40 mmol) was added at 0° C. The reaction mixturewas stirred at RT for 16 h. Volatiles were removed under reducedpressure. The residue was dissolved in DCM (5 mL) and TFA (36.10 mmol)was added. The reaction mixture was stirred at RT for 1 h and thenconcentrated under reduced pressure. The residue was dissolved in EtOH(10 mL) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76mmol) and triethylamine (3.80 mmol) were added. The reaction mixture washeated to 80° C. for 16 h, cooled and concentrated under reducedpressure. Further purification gave the titled compound (0.19 mmol) as abrown solid. UPLC-MS: (ES⁺, Short acidic): 2.09 min, m/z 405.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazole-4-carbonitrile(0.19 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.27 mmol) gave,after purification, the titled compound (0.08 mmol) as a yellow solid.UPLC-MS: (ES⁺, Short acidic): 1.78 min, m/z 488.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.08 mmol) gave, after purification, the titled compound (0.03 mmol) asa white solid. UPLC-MS: (ES⁺, Short acidic): 1.57 min, m/z 506.2 [M+H]⁺.UPLC-MS: (ES⁺, Long acidic): 3.63 min, m/z 506.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.6, 1.7 Hz, 1H),7.50-7.39 (m, 5H), 7.15 (d, J=7.9 Hz, 1H), 7.06-7.02 (m, 1H), 6.48 (s,2H), 4.75-4.67 (m, 1H), 4.54 (d, J=6.2 Hz, 2H), 3.90 (s, 3H), 1.74 (d,J=7.8 Hz, 4H), 1.34 (s, 6H), 1.15 (s, 6H).

Example 91:3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

3-(4-Bromophenyl)-5-(methylamino)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

5-Amino-3-(4-bromophenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.86 mmol) dissolved in MeOH (8 mL), paraformaldehyde (2.57 mmol) andsodium methoxide (25 wt % in MeOH, 5.15 mmol) were heated at 70° C. for1 h, then allowed to cool back down to RT. Sodium borohydride (8.58mmol) was added and the reaction was stirred at RT for 16 h, thencarefully quenched with water. The aqueous layer was extracted with DCM(3×20 mL), and the combined organic layers were filtered over ahydrophobic frit, and concentrated under reduced pressure. Purificationgave the titled compound (0.65 mmol) as a white solid. UPLC-MS (ES⁺,Short acidic): 1.80 min, m/z 362.9 [M+2]⁺

N-[[4-[4-Cyano-5-(methylamino)-1-tetrahydropyran-4-yl-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-5-(methylamino)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.65 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.71 mmol) gave,after purification, the titled compound (0.44 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 446.1 [M+H]⁺

3-[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure L,N-[[4-[4-cyano-5-(methylamino)-1-tetrahydropyran-4-yl-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.44 mmol) gave, after purification, the titled compound (0.04 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 464.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.08 min, m/z 464.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.71 (t, J=6.6 Hz, 1H), 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.54(d, J=8.1 Hz, 2H), 7.48 (td, J=8.4, 1.8 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H),7.15 (d, J=8.3 Hz, 1H), 7.04 (td, J=8.1, 0.7 Hz, 1H), 6.7 (br s, 1H),5.80 (q, J=5.2 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H), 4.42-4.34 (m, 1H), 3.97(dd, J=11.2, 3.8 Hz, 2H), 3.90 (s, 3H), 3.53-3.40 (m, 2H), 2.84 (d,J=5.6 Hz, 3H), 2.12-2.00 (m, 2H), 1.80-1.77 (m, 2H).

Example 92:5-amino-1-cyclopentyl-3-[3-fluoro-4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[(4-Bromo-2-fluoro-phenyl)methyl]-2-methoxy-5-methyl-benzamide

A solution of (4-bromo-2-fluoro-phenyl)methanamine (5.00 mmol) in THF (4mL), a propylphosphonic anhydride solution (50 wt % in EtOAc, 7.50 mmol)in THF (6 mL), 2-methoxy-5-methylbenzoic acid (6.04 mmol), andN,N-diisopropylethylamine (8.88 mmol) was stirred at 80° C. for 18 h.The reaction was cooled to RT and partitioned between EtOAc and asaturated aqueous solution of NH₄Cl. The organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified to give the titled compound(3.51 mmol). UPLC-MS (ES⁺, Short acidic): 2.05 min, m/z 353.9 [M+2]⁺

N-[[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-5-methyl-benzamide

General procedure R,N-[(4-bromo-2-fluoro-phenyl)methyl]-2-methoxy-5-methyl-benzamide (3.51mmol) gave, after purification, the titled compound (3.51 mmol). UPLC-MS(ES⁺, Short acidic): 2.18 min, m/z 400.1 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)-2-(fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide

General procedure D,N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-5-methyl-benzamide(3.51 mmol) gave, after purification, the titled compound (1.03 mmol).UPLC-MS (ES⁺, Short acidic): 1.86 min, m/z 380.0 [M+H]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide

Cesium carbonate (1.34 mmol),N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide(1.03 mmol) and bromocyclopentane (1.13 mmol) in DMF (10 mL) werestirred at 80° C. for 3.5 h, then cooled to RT and partitioned betweenwater and EtOAc. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure.Further purification gave the titled compound (0.07 mmol). UPLC-MS (ES⁺,Short acidic): 2.21 min, m/z 448.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[3-fluoro-4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide(0.07 mmol) gave, after purification, the titled compound (0.02 mmol,24% yield). UPLC-MS (ES⁺, Short acidic): 2.10 min, m/z 466.2 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.88 min, m/z 466.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.68 (t, J=6.0 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.41 (t,J=7.9 Hz, 1H), 7.34-7.30 (dd, J=7.9, 1.5 Hz, 1H), 7.30-7.28 (m, 1H),7.28-7.25 (m, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.25 (s, 2H), 4.65-4.60 (m,1H), 4.56 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 2.27 (s, 3H), 2.03-1.85 (m,4H), 1.83-1.72 (m, 2H), 1.65-1.52 (m, 2H).

Example 93:5-amino-1-cyclopentyl-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

2-[(4-Bromo-3-fluoro-phenyl)-hydroxy-methylene]propanedinitrile

General procedure W, 4-bromo-3-fluorobenzoyl chloride (5.29 mmol) andmalononitrile (0.37 mL, 5.81 mmol) gave the titled compound (5.15 mmol)as a pale brown solid. UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 266.9[M]⁺

2-[(4-Bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile

General procedure X,2-[(4-bromo-3-fluoro-phenyl)-hydroxy-methylene]propanedinitrile (5.11mmol) and dimethyl sulfate (15.3 mmol) gave, after purification, thetitled compound (1.62 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆,δ): 8.06-8.02 (m, 1H), 7.86 (dd, J=9.1, 1.9 Hz, 1H), 7.54-7.52 (m, 1H),3.92 (s, 3H).

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (200 mg,0.71 mmol) and cyclopentylhydrazine hydrochloride (117 mg, 0.85 mmol)gave, after purification, the titled compound (0.48 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 2.06 min, m/z 348.9 [M]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.46 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.69 mmol) gave,after purification, the titled compound (0.19 mmol) as a pale brownsolid. UPLC-MS (ES⁺, Short acidic): 1.80 min, m/z 434.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.18 mmol) gave, after purification, the titled compound (0.07 mmol) asa light brown solid. UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 452.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.66 min, m/z 452.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.71 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.6, 1.8 Hz,1H), 7.51-7.47 (m, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.34-7.27 (m, 2H), 7.16(d, J=8.2 Hz, 1H), 7.07-7.03 (m, 1H), 6.26 (s, 2H), 4.68-4.60 (m, 1H),4.57 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.01-1.88 (m, 4H), 1.84-1.76 (m,2H), 1.63-1.55 (m, 2H).

Example 94:5-amino-1-[trans-4-hydroxytetrahydrofuran-3-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

trans-4-Hydrazinotetrahydrofuran-3-ol

To a solution of 3,6-dioxabicyclo[3.1.0]hexane (11.62 mmol) in EtOH (39mL), cooled to 0° C., was added dropwise hydrazine hydrate (55-60% inwater, 29.04 mmol). The reaction was stirred at RT for 10 min and thenheated at 60° C. for 16 h. The reaction was concentrated under reducedpressure to give crude the titled compound (11.61 mmol). ¹H NMR (400MHz, DMSO-d₆, δ): 4.06-4.02 (m, 1H), 3.80-3.71 (m, 2H), 3.52-3.43 (m,2H), 3.07-3.02 (m, 1H).

5-Amino-3-(4-bromophenyl)-1-[trans-4-hydroxytetrahydrofuran-3-yl]pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (5.7 mmol) andtrans-4-hydrazinotetrahydrofuran-3-ol (6.97 mmol) gave, afterpurification, the titled compound (5.09 mmol). ¹H NMR (400 MHz, DMSO-d₆,δ): 7.77-7.64 (m, 4H), 6.85 (m, 2H), 5.52 (d, J=4.1 Hz, 1H), 4.71-4.66(m, 1H), 4.61-4.55 (m, 1H), 4.17-4.11 (m, 1H), 4.09-4.04 (m, 1H),3.82-3.77 (m, 1H), 3.67-3.61 (m, 1H).

5-Amino-3-(4-bromophenyl)-1-[trans-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]pyrazole-4-carbonitrile

To a solution of5-amino-3-(4-bromophenyl)-1-[trans-4-hydroxytetrahydrofuran-3-yl]pyrazole-4-carbonitrile(1.43 mmol) in DMF (7.2 mL) was added imidazole (3.44 mmol), andtert-butyl-chlorodimethylsilane (3.15 mmol). The reaction was heated at50° C. for 16 h, cooled and then partitioned between water and EtOAc.The organic layer was washed with water, dried over sodium sulfatefiltered and then concentrated under reduced pressure. Furtherpurification gave the titled compound (0.54 mmol). UPLC-MS (ES⁺, Shortacidic): 2.27 min, m/z 465.0 [M+2]⁺

N-[[4-[5-Amino-1-[trans-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.76 mmol) and5-amino-3-(4-bromophenyl)-1-[trans-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]pyrazole-4-carbonitrile(0.54 mmol) gave, after purification, the titled compound (0.39 mmol,72% yield). UPLC-MS (ES⁺, Short acidic): 2.00 min, m/z 548.2 [M]⁺

5-Amino-1-[trans-4-hydroxytetrahydrofuran-3-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-1-[trans-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.23 mmol) gave, after purification, the titled compound (0.04 mmol).

UPLC-MS (ES⁺, Long acidic): 2.74 min, m/z 452.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7, 1.8 Hz, 1H),7.51-7.39 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.06-7.02 (m, 1H), 6.40 (brs, 2H), 5.46 (d, J=4.2 Hz, 1H), 4.69-4.62 (m, 1H), 4.57-4.51 (m, 3H),4.15 (dd, J=9.0, 6.9 Hz, 1H), 4.00 (dd, J=9.3, 5.3 Hz, 1H), 3.90 (s,3H), 3.81 (dd, J=9.2, 4.6 Hz, 1H), 3.62 (dd, J=9.1, 2.2 Hz, 1H).

Example 95:5-amino-1-[3-fluorotetrahydropyran-4-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(Isomer 1)

tert-Butyl N-[(3-(fluorotetrahydropyran-4-ylidene)amino]carbamate

General procedure E, 3-fluorodihydro-2H-pyran-4(3H)-one (1.48 mmol) andtert-butyl carbazate (2.22 mmol) gave crude the titled compound (1.48mmol).

¹H NMR (400 MHz, CDCl₃, δ): 7.79 (s, 1H), 5.00 (d, J=47.8 Hz, 1H), 4.33(d, J=13.7 Hz, 1H), 4.20-4.13 (m, 1H), 3.79-3.63 (m, 1H), 3.54-3.45 (m,1H), 2.68-2.57 (m, 1H), 2.53-2.45 (m, 1H), 1.54 (s, 9H).

5-Amino-3-(4-bromophenyl)-1-(3-fluorotetrahydropyran-4-yl)pyrazole-4-carbonitrile

General procedure O, tert-butylN-[(3-fluorotetrahydropyran-4-ylidene)amino]carbamate (1.48 mmol) in THF(4.9 mL) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.99mmol) gave, after purification, the titled compound (isomer 1, 0.50mmol) and the titled compound (isomer 2, 0.22 mmol). UPLC-MS (ES⁺, Shortacidic, isomer 1): 1.66 min, m/z 366.9 [M+2]⁺. UPLC-MS (ES⁺, Shortacidic, isomer 2): 1.77 min, m/z 366.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3-fluorotetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(Isomer 1)

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.70 mmol) and5-amino-3-(4-bromophenyl)-1-(3-fluorotetrahydropyran-4-yl)pyrazole-4-carbonitrile(isomer 1, 0.50 mmol) gave, after purification, the titled compound(isomer 1, 0.40 mmol). UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 450.1[M+H]⁺

5-Amino-1-[3-fluorotetrahydropyran-4-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(Isomer 1)

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-fluorotetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 1, 0.40 mmol) gave, after purification, the titled compound(isomer 1, 0.13 mmol) as a white solid. UPLC-MS (ES⁺, Long acidic): 2.92min, m/z 468.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.2 Hz,1H), 7.75 (dd, 7=7.6, 1.7 Hz, 1H), 7.51-7.39 (m, 5H), 7.15 (d, J=8.1 Hz,1H), 7.05-7.03 (m, 1H), 6.45 (br s, 2H), 4.94-4.74 (m, 1H), 4.62-4.48(m, 3H), 4.09-3.98 (m, 2H), 3.90 (s, 3H), 3.72-3.44 (m, 2H), 2.63 (dd,J=13.0, 4.9 Hz, 1H), 1.81-1.71 (m, 1H).

Example 96:5-amino-1-[3-fluorotetrahydropyran-4-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(Isomer 2)

N-[[4-[5-Amino-4-cyano-1-(3-fluorotetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzaimde(Isomer 2)

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.31 mmol) and5-amino-3-(4-bromophenyl)-1-(3-fluorotetrahydropyran-4-yl)pyrazole-4-carbonitrile(isomer 2, 0.22 mmol) gave, after purification, the titled compound(isomer 2, 0.16 mmol, 72% yield). UPLC-MS (ES⁺, Short acidic): 1.54 min,m/z 450.1 [M+H]⁺

5-Amino-1-[3-fluorotetrahydropyran-4-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(Isomer 2)

General procedure L,N-[[4-[5-amino-4-cyano-1-(3-fluorotetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 2, 0.16 mmol) gave after purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM and furtherrecrystallization from DCM,5-amino-1-[3-fluorotetrahydropyran-4-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(isomer 2, 0.02 mmol).

UPLC-MS (ES⁺, Long acidic): 3.09 min, m/z 468.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.6 Hz, 1H),7.52-7.40 (m, 5H), 7.16 (d, J=8.2 Hz, 1H), 7.04 (t, J=7.7 Hz, 1H), 6.45(br s, 2H), 5.03-4.82 (m, 1H), 4.65-4.52 (m, 3H), 4.18 (dd, J=10.6, 5.4Hz, 1H), 3.97-3.91 (m, 1H), 3.91 (s, 3H), 3.49-3.38 (m, 1H), 3.33 (m,1H), 2.09-1.91 (m, 2H).

Example 97:3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

3-(4-Bromophenyl)-5-(methylamino)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

Following general procedure W,5-amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(100 mg, 0.30 mmol) gave, after purification, the titled compound (64mg, 0.18 mmol, 61% yield) as a white solid. UPLC-MS: (ES⁺, Shortacidic): 1.80 min, m/z 348.9 [M+2]⁺

N-[[4-[4-Cyano-5-(methylamino)-1-tetrahydrofuran-3-yl-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-5-(methylamino)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.18 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.27 mmol) gave,after purification, the titled compound (0.18 mmol) as a yellow solid.UPLC-MS: (ES⁺, Short acidic): 1.58 min, m/z 432.1 [M+H]⁺

3-[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Following general procedure L,N-[[4-[4-cyano-5-(methylamino)-1-tetrahydrofuran-3-yl-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.13 mmol) gave, after purification, the titled compound (0.03 mmol) asa white solid. UPLC-MS: (ES⁺, Short acidic): 1.36 min, m/z 450.1 [M+H]⁺.UPLC-MS: (ES⁺, Long acidic): 3.08 min, m/z 450.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆, □): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.6, 1.6 Hz, 1H),7.54 (d, J=8.2 Hz, 2H), 7.51-7.44 (m, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.15(d, J=8.3 Hz, 1H), 7.06-7.02 (m, 1H), 5.92 (q, J=5.4 Hz, 1H), 5.04-4.95(m, 1H), 4.53 (d, J=5.9 Hz, 2H), 4.07-3.95 (m, 2H), 3.90 (s, 3H),3.88-3.79 (m, 2H), 2.85 (d, J=5.5 Hz, 3H), 2.33-2.24 (m, 2H).

Example 98:5-amino-1-(3,4-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(3,4-difluorophenyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol) and(3,4-difluorophenyl)hydrazinium chloride (0.68 mmol) gave, afterpurification, the titled compound (0.30 mmol, 53% yield) as a whitesolid.

UPLC-MS (ES⁺, Short acidic): 1.96 min, m/z 376.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(3,4-difluorophenyl)pyrazole-4-carbonitrile(0.30 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.46 mmol) gave,after purification, the titled compound (0.08 mmol) as a beige solid.UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 460.1 [M+H]⁺

5-Amino-1-(3,4-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(3,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.08 mmol) gave, after purification, the titled compound (0.02 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 478.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.60 min, m/z 478.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.1 Hz, 1H), 7.77-7.70 (m, 2H),7.66-7.44 (m, 7H), 7.17-7.15 (m, 1H), 7.07-7.02 (m, 1H), 6.59 (s, 2H),4.57 (d, J=6.0 Hz, 2H), 3.91 (s, 3H)

Example 99:5-amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

2-[(4-Bromo-2-fluoro-phenyl)-hydroxy-methylene]propanedinitrile

General procedure W, 4-bromo-2-fluoro benzoyl chloride (14.1 mmol) andmalononitrile (15.5 mmol) gave crude the titled compound (14.1 mmol).UPLC-MS (ES⁻, Short acidic): 1.21 min, m/z 266.7 [M]⁻

2-[(4-Bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile

General procedure X,2-[(4-bromo-2-fluoro-phenyl)-hydroxy-methylene]propanedinitrile (14.6mmol) gave, after purification, the titled compound (10.52 mmol) as awhite solid. UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 280.8 [M]⁺

5-Amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.92mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.11 mmol)afforded, after purification, the titled compound (0.82 mmol) as acolourless film. UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 366.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.74 mmol) and5-amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.49 mmol) gave, after purification, the titled compound (0.28 mmol) asan off-white solid. UPLC-MS (ES+, Short acidic): 1.48 min, m/z 450.1[M+H]⁺

5-Amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.28 mmol) afforded, after purification, the titled compound (0.09mmol) as a white solid. UPLC-MS (ES+, Short acidic): 1.31 min, m/z 468.1[M+H]⁺. UPLC-MS (ES+, Long acidic): 2.96 min, m/z 468.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □): 8.79 (t, J=6.1 Hz, 1H), 7.73 (dd, J=7.7, 1.8 Hz,1H), 7.51-7.47 (m, 1H), 7.40 (dd, J=8.2, 7.5 Hz, 1H), 7.27-7.22 (m, 2H),7.16 (dd, J=8.3, 0.6 Hz, 1H), 7.07-7.03 (m, 1H), 6.34 (s, 2H), 4.55 (d,J=6.1 Hz, 2H), 4.41-4.31 (m, 1H), 3.99-3.92 (m, 2H), 3.90 (s, 3H),3.46-3.38 (m, 2H), 2.02-1.89 (m, 2H), 1.82-1.73 (m, 2H).

Example 100:5-amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.77mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (0.92 mmol) gave,after purification, the titled compound (0.69 mmol) as a colourlessfilm. UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 352.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.48 mmol) and5-amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.37 mmol) gave, after purification, the titled compound (0.23 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 436.0[M+H]⁺

5-Amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide(98 mg, 0.23 mmol) afforded, after purification, the titled compound (42mg, 0.09 mmol, 41% yield) as a white solid. UPLC-MS (ES+, Short acidic):1.31 min, m/z 454.1 [M+H]⁺. UPLC-MS (ES+, Long acidic): 2.96 min, m/z454.1 M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.78 (t, J=6.0 Hz, 1H), 7.73(dd, J=7.7, 1.8 Hz, 1H), 7.51-7.47 (m, 1H), 7.40 (dd, J=8.1, 7.6 Hz,1H), 7.27-7.22 (m, 2H), 7.18-7.13 (m, 1H), 7.06-7.04 (m, 1H), 6.36 (s,2H), 4.98-4.90 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 4.01-3.91 (m, 2H), 3.90(s, 3H), 3.82-3.75 (m, 2H), 2.29-2.20 (m, 2H)

Example 101:5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]-2-methyl-phenyl]pyrazole-4-carboxamide

(4-Bromo-3-methyl-phenyl)methanamine

A solution of 4-bromo-3-methylbenzonitrile (5.10 mmol) in THF (30 mL)and a borane dimethyl sulfide complex solution (2 M in THF, 15.30 mmol)was stirred at 0° C. for 30 min before being warmed to RT and stirredfor 18 h. The reaction was quenched with MeOH (30 mL) and wasconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and a 1 M aqueous solution of NaOH. The organic layer was washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure to afford crude the titled compound (5.10 mmol). ¹H NMR(400 MHz, CDCl₃, δ): 7.43-7.50 (m, 1H), 7.21-7.15 (m, 1H), 6.95-7.03 (m,1H), 3.80 (s, 2H), 2.39 (s, 3H).

N-[(4-Bromo-3-methyl-phenyl)methyl]-2-methoxy-benzamide

(4-Bromo-3-methyl-phenyl)methanamine (5.10 mmol) dissolved in THF (20mL) and N,N-diisopropylethylamine (15.29 mmol) was cooled to 0° C.before addition of 2-methoxybenzoyl chloride (5.61 mmol) and thenstirred at 0° C. for 20 min. The reaction was warmed to RT and stirredfor 66 h. The reaction was quenched with a saturated aqueous solution ofNH₄Cl and concentrated under reduced pressure. The residue was extractedwith EtOAc and washed with brine. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure.Purification gave the titled compound (5.10 mmol). UPLC-MS (ES⁺, Shortacidic): 2.01 min, m/z 335.9 [M+2]⁺

2-Methoxy-N-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

General procedure R,N-[(4-bromo-3-methyl-phenyl)methyl]-2-methoxy-benzamide (5.1 mmol) gave,after purification, the titled compound (3.82 mmol). UPLC-MS (ES⁺, Shortacidic): 2.15 min, m/z 382.1 [M+H]⁺

3-Amino-5-bromo-1H-pyrazole-4-carbonitrile

A solution of 3-amino-4-cyanopyrazole (46.25 mmol) in MeCN (180 mL) andN-bromosuccinimide (60.1 mmol) at 0° C. was warmed up to RT and stirredfor 16 h. The reaction was concentrated under reduced pressure and theresidue purified to give the titled compound (22.4 mmol). UPLC-MS (ES⁺,Short acidic): 0.98 min, m/z 188.8 [M+2]⁺

5-Amino-3-bromo-1-cyclopentyl-pyrazole-4-carbonitrile

Cesium carbonate (33.6 mmol), 3-amino-5-bromo-1H-pyrazole-4-carbonitrile(22.4 mmol) and bromocyclopentane (2.64 mL, 24.6 mmol) in MeCN (170 mL)was stirred at 80° C. for 19 h, then cooled to RT and partitionedbetween water and EtOAc. The organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.Purification gave the titled compound (1.00 g, 3.92 mmol, 18% yield).UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 256.9 [M+2]⁺

5-Amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide

General procedure M,5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carbonitrile (3.92 mmol) gave,after purification, the titled compound (2.87 mmol). UPLC-MS (ES⁺, Shortacidic): 1.32 min, m/z 274.8 [M+2]⁺

5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]-2-methyl-phenyl]pyrazole-4-carboxamide

A mixture of potassium carbonate (2.40 mmol),2-methoxy-N-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(0.60 mmol) and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide(0.57 mmol) in EtOH (3 mL) and water (0.6 mL) was purged and degassedwith nitrogen.[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.12mmol) was added. The solution was sealed and heated to 120° C. for 1 hin the microwave. The reaction was then filtered through a pad ofCelite® and washed with DCM, then concentrated under reduced pressure.Purification gave the titled compound (0.06 mmol). UPLC-MS (ES⁺, Shortacidic): 1.55 min, m/z 448.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.59min, m/z 448.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.71 (t, J=6.1 Hz,1H), 7.74 (dd, J=7.5, 1.9 Hz, 1H), 7.50-7.45 (m, 1H), 7.29 (s, 1H),7.27-7.19 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 7.03 (td, J=7.5, 1.0 Hz, 1H),6.37 (s, 2H), 4.66-4.58 (m, 1H), 4.52 (d, J=6.1 Hz, 2H), 3.89 (s, 3H),2.13 (s, 3H), 2.01-1.92 (m, 2H), 1.92-1.82 (m, 2H), 1.81-1.71 (m, 2H),1.63-1.52 (m, 2H).

Example 102:5-amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.82mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (0.99 mmol) gave,after purification, the titled compound (0.42 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 366.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.63 mmol) and5-amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.42 mmol) gave, after purification, the titled compound (0.16 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 450.0[M+H]⁺

5-Amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.28 mmol) afforded, after purification, the titled compound (0.03mmol, 11% yield) as a white solid. UPLC-MS (ES+, Short acidic): 1.37min, m/z 468.1 [M+H]⁺. UPLC-MS (ES+, Long acidic): 3.12 min, m/z 468.1M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.78 (t, J=6.1 Hz, 1H), 7.73 (dd,J=7.6, 1.7 Hz, 1H), 7.51-7.46 (m, 1H), 7.40 (dd, J=8.2, 7.5 Hz, 1H),7.27-7.21 (m, 2H), 7.16 (dd, J=8.3, 0.6 Hz, 1H), 7.04 (td, J=7.5, 1.0Hz, 1H), 6.37 (s, 2H), 4.55 (d, J=6.1 Hz, 2H), 4.32-4.22 (m, 1H), 3.90(s, 3H), 3.89-3.80 (m, 2H), 3.52 (dd, J=10.5 Hz, 1H), 3.35-3.25 (m, 1H),2.02-1.94 (m, 2H), 1.77-1.61 (m, 2H)

Example 103:5-amino-1-(2-fluorocyclopentyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(2-fluorocyclopentylidene)amino]carbamate

A solution of N-fluorobenzenesulfonimide (1.85 mmol) and1-(trimethylsiloxy)cyclopentene (1.69 mmol) in THF (8 mL) at RT wasstirred at RT for 5 h, then tert-butyl carbazate (1.69 mmol) was added.The reaction was stirred at RT for an additional 16 h, then concentratedunder reduced pressure. Further purification gave the titled compound(1.20 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.41min, m/z 217 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-(2-fluorocyclopentyl)pyrazole-4-carbonitrile

General procedure O at RT, tert-butylN-[(2-fluorocyclopentylidene)amino]carbamate (1.20 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.80 mmol) gave,after purification, the titled compound (0.24 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.89 min, m/z 350.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2-fluorocyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2-fluorocyclopentyl)pyrazole-4-carbonitrile(0.24 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.28 mmol) gave,after purification, the titled compound (0.24 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 434.0 [M+H]⁺

5-Amino-1-(2-fluorocyclopentyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2-fluorocyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.24 mmol) gave, after purification, the titled compound (0.09 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 452.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.38 min, m/z 452.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.7, 1.7 Hz, 1H),7.52-7.38 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.08-7.01 (m, 1H), 6.39 (s,2H), 5.27-5.07 (m, 1H), 4.60-4.45 (m, 3H), 3.90 (s, 3H), 2.65-2.41 (m,1H), 2.09-1.83 (m, 4H), 1.76-1.55 (m, 1H).

Example 104:5-amino-1-(2,6-dimethyltetrahydropyran-4-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(2,6-dimethyltetrahydropyran-4-ylidene)amino]carbamate

Following general procedure E, 2,6-dimethyloxan-4-one (200 mg, 1.56mmol) and tert-butyl carbazate (217 mg, 1.64 mmol) gave, afterpurification, the titled compound (0.88 mmol) as an off-white solid. ¹HNMR (400 MHz, CDCl₃, □): 7.52 (s, 1H), 3.69-3.61 (m, 1H), 3.59-3.51 (m,1H), 2.59-2.50 (m, 2H), 2.13-2.07 (m, 1H), 1.82-1.75 (m, 1H), 1.53 (s,9H), 1.33 (d, J=6.0 Hz, 3H), 1.28 (d, J=5.9 Hz, 3H)

5-Amino-3-(4-bromophenyl)-1-(2,6-dimethyltetrahydropyran-4-yl)pyrazole-4-carbonitrile

General procedure O, tert-ButylN-[(2,6-dimethyltetrahydropyran-4-ylidene)amino]carbamate (0.88 mmol)and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol)gave, after purification, the titled compound (0.29 mmol) as a brownsolid. UPLC-MS: (ES⁺, Short acidic): 1.91 min, m/z 376.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,6-dimethyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,6-dimethyltetrahydropyran-4-yl)pyrazole-4-carbonitrile(0.29 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.61 mmol) gave,after purification, the titled compound (0.25 mmol) as a brown solid.UPLC-MS: (ES⁺, Short acidic): 1.63 min, m/z 460.1 [M+H]⁺

5-Amino-1-(2,6-dimethyltetrahydropyran-4-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2,6-dimethyltetrahydropyran-4-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.25 mmol) gave, after purification, the titled compound (0.02 mmol) asan off-white solid. UPLC-MS: (ES⁺, Short acidic): 1.42 min, m/z 478.2[M+H]⁺. UPLC-MS: (ES⁺, Short acidic): 3.26 min, m/z 478.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □): 8.73 (t, J=6.2 Hz, 1H), 7.75 (dd, J=7.6, 1.7 Hz,1H), 7.50-7.39 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.06-7.02 (m, 1H), 6.36(s, 2H), 4.54 (d, J=6.1 Hz, 2H), 4.43-4.35 (m, 1H), 3.90 (s, 3H),3.59-3.52 (m, 2H), 1.83-1.79 (m, 2H), 1.62-1.53 (m, 2H), 1.14 (d, J=6.1Hz, 6H)

Example 105:5-amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.31 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.34mmol) afforded, after purification, the titled compound (0.33 mmol) as ayellow oil. UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 454.1 [M+H]⁺

5-Amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.33 mmol) gave, after purification, the titled compound (0.06 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 472.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.08 min, m/z 472.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.89 (t, J=6.1 Hz, 1H), 7.50 (dd, J=9.2, 3.3 Hz, 1H),7.43-7.32 (m, 2H), 7.26-7.18 (m, 3H), 6.37 (s, 2H), 4.98-4.91 (m, 1H),4.56 (d, J=6.1 Hz, 2H), 4.01-3.92 (m, 2H), 3.90 (s, 3H), 3.82-3.77 (m,2H), 2.30-2.21 (m, 2H).

Example 106:5-amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2methoxy-benzaimde

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.30 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.33mmol) afforded, after purification, the titled compound (0.31 mmol) as ayellow oil. UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 468.1 [M+H]⁺

5-Amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.31 mmol) afforded, after purification, the titled compound (0.10mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 486.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.08 min, m/z 486.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.89 (t, J=6.1 Hz, 1H), 7.50 (dd, J=9.2, 3.3 Hz1H), 7.43-7.32 (m, 2H), 7.26-7.18 (m, 3H), 6.35 (s, 2H), 4.56 (d, J=6.1Hz, 2H), 4.41-4.34 (m, 1H), 3.99-3.95 (m, 2H), 3.91 (s, 3H), 3.48-3.36(m, 2H), 2.01-1.91 (m, 2H), 1.80-1.70 (m, 2H).

Example 107:5-amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.19 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.28mmol) afforded, after purification, the titled compound (0.21 mmol,assumed quantitative yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 468.1 [M+H]⁺

5-Amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.21 mmol) afforded, after purification, the titled compound (0.06mmol) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z486.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 486.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆, δ): 8.89 (t, J=6.1 Hz, 1H), 7.50 (dd, J=9.1, 3.3Hz, 1H), 7.42-7.32 (m, 2H), 7.26-7.18 (m, 3H), 6.38 (s, 2H), 4.56 (d,J=6.1 Hz, 2H), 4.32-4.24 (m, 1H), 3.91 (s, 3H), 3.87-3.83 (m, 2H), 3.31(m, 2H), 2.02-1.96 (m, 2H), 1.76-1.66 (m, 2H).

Example 108:5-(difluoromethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

Ethyl-4,4-difluoro-2-(methoxymethylene)-3-oxo-butanoate

A solution of anhydrous trimethyl orthoformate (15.3 mmol) and ethyl4,4-difluoro-3-oxobutanoate (7.64 mmol) in acetic anhydride (3 mL) washeated at 90° C. for 16 h under Dean-Stark conditions, cooled andconcentrated under reduced pressure to afford crude the titled compound(7.30 mmol) as a brown oil. ¹H NMR (400 MHz, CDCl₃, δ, mixture ofisomers): 7.81 (s, 0.5H), 7.79 (s, 0.5H), 6.58-6.22 (m, 1H), 4.39-4.25(m, 2H), 4.15 (s, 1.5H), 4.12 (s, 1.5H), 1.38-1.31 (m, 3H).

Ethyl 5-(difluoromethyl)-1H-pyrazole-4-carboxylate

A solution of ethyl-4,4-difluoro-2-(methoxymethylene)-3-oxo-butanoate(2.40 mmol) in MeOH (8 mL) and hydrazine hydrate (55-60% in water, 2.40mmol) was stirred at RT for 16 h. Then all volatiles were removed underreduced pressure. The residue was diluted in EtOAc. The layers werepartitioned and the organic layer was washed successively with water(×2) then brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford crude the titled compound (1.81 mmol,75% yield) as a yellow oil. UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z190.9 [M+H]⁺

Ethyl 3-bromo-5-(difluoromethyl)-1H-pyrazole-4-carboxylate

N-Bromosuccinimide (2.36 mmol) was added portionwise to a solution ofethyl 5-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.81 mmol) in MeCN(6 mL). The resulting mixture was then stirred at 80° C. for 72 h. Thenthe solvent was removed under reduced pressure. The crude product waspurified to give the titled compound (1.38 mmol) as a yellow oil.UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 268.8 [M]⁺

Ethyl3-bromo-5-(difluoromethyl)-1-tetrahydropyran-4-yl-pyrazole-4-carboxylate

4-Bromotetrahydro-2H-pyran (0.17 mL, 1.51 mmol) was added to asuspension of potassium carbonate (1.51 mmol) and ethyl3-bromo-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.38 mmol) in MeCN(2.7 mL). The reaction mixture was heated at 90° C. for 16 h thenpartitioned between water and DCM. The aqueous layer was extracted withDCM (×3), and the combined organic phases were filtered over ahydrophobic frit and concentrated under reduced pressure. Furtherpurification gave the titled compound (0.50 mmol), which containedtraces of the other regioisomer, as an off-white solid. UPLC-MS (ES⁺,Short acidic): 1.67 min, m/z 354.9 [M+2]⁺ and 1.78 min, m/z 352.9 [M]⁺

3-Bromo-5-(difluoromethyl)-1-tetrahydropyran-4-yl-pyrazole-4-carboxylicacid

An aqueous solution of NaOH (1 M, 0.85 mmol) was added to a solution ofethyl3-bromo-5-(difluoromethyl)-1-tetrahydropyran-4-yl-pyrazole-4-carboxylate(0.28 mmol) in THF (1.3 mL). The reaction mixture was heated at 50° C.for 16 h, cooled to RT, acidified to ˜pH 1 with hydrochloric acid (1 M),and then extracted with DCM (×3). The combined organic layers werefiltered over a hydrophobic frit and concentrated under reducedpressure. Purification gave the titled compound (0.10 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 326.9 [M+2]⁺

3-Bromo-5-(difluoromethyl)-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

A drop of DMF was added to a solution of oxalyl chloride (0.02 mL, 0.25mmol) and3-bromo-5-(difluoromethyl)-1-tetrahydropyran-4-yl-pyrazole-4-carboxylicacid (0.10 mmol) in DCM (1 mL) at RT. The reaction mixture was stirredat RT for 1 h then cooled to 0° C., and ammonium hydroxide (28 wt % inwater, 1.01 mmol) was added carefully. The reaction mixture was stirredat RT for 20 min, then partitioned between water and DCM. The aqueouslayer was extracted with DCM (×3) and the combined organic layers werefiltered over a hydrophobic frit and concentrated under reducedpressure. Purification gave the titled compound (0.08 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 325.9 [M+2]⁺

5-(Difluoromethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure C, [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronicacid (0.12 mmol) and3-bromo-5-(difluoromethyl)-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide(0.08 mmol) gave, after purification, the titled compound (0.05 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 485.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.42 min, m/z 485.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz, 1H),7.70-7.61 (m, 3H), 7.58 (br s, 1H), 7.52-7.45 (m, 1H), 7.40 (d, J=8.4Hz, 2H), 7.34 (t, J=52.3 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.08-7.01 (m,1H), 4.67-4.56 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 4.05-3.96 (m, 2H), 3.91(s, 3H), 3.55-3.45 (m, 2H), 2.26-2.10 (m, 2H), 1.95-1.82 (m, 2H).

Example 109:5-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

tert-Butyl) N-[tetrahydrofuran-3-ylideneamino]carbamate

General procedure E, dihydro(3(2H)-furanone (0.15 mL, 1.95 mmol) andtert-butyl carbazate (2.35 mmol) gave crude the titled compound (2.02mmol) as a white solid. ¹H NMR (400 MHz, CDCl₃, □): 7.23 (s, 1H),4.35-4.34 (m, 2H), 4.09 (t, J=6.9 Hz, 2H), 2.50-2.46 (m, 2H), 1.52 (s,9H).

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

To a solution of tert-butyl N-[tetrahydrofuran-3-ylideneamino]carbamate(0.25 mmol) in THF (5 mL) was added a borane dimethyl sulfide complexsolution (2 M in THF, 0.42 mmol). The reaction mixture was stirred at RTfor 1 h then concentrated under reduced pressure. A hydrogen chloridesolution in MeOH (1.25 M, 8.74 mmol) was added to the residue and thereaction mixture was heated under reflux for 16 h. The mixture wascooled to RT, and concentrated under reduced pressure. The residue wastaken up with EtOH (10 mL) and2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.71mmol) and triethylamine (0.50 mL, 3.56 mmol) were added. The reactionmixture was heated at reflux for 3 h, cooled, and filtered. The solidwas washed with EtOH and EtOAc. The filtrate was evaporated to drynessand the obtained solid washed with EtOAc. The combined solids affordedthe titled compound (0.71 mmol) as an off-white solid. UPLC-MS: (ES⁺,Short acidic): 1.72 min, m/z 352.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.68 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.96 mmol) gave,after purification, the titled compound (0.47 mmol) as a yellow solid.UPLC-MS: (ES⁺, Short acidic): 1.54 min, m/z 436.1 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

A modified general procedure L for 96 h,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.23 mmol) gave, after purification, the titled compound (80 mg, 0.18mmol, 77% yield) as a white solid. UPLC-MS: (ES⁺, Short acidic): 1.35min, m/z 454.1 [M+H]⁺. UPLC-MS: (ES⁺, Long acidic): 3.07 min, m/z 454.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.17 (t, J=5.9 Hz, 1H), 7.75 (d,J=7.7, 1.7 Hz, 1H), 7.51-7.41 (m, 2H), 7.34-7.28 (m, 2H), 7.16 (d, J=8.3Hz, 1H), 7.06-7.02 (m, 1H), 6.34 (s, 2H), 4.96-4.91 (m, 1H), 4.57 (d,J=5.9 Hz, 2H), 4.00-3.93 (m, 2H), 3.90 (s, 3H), 3.83-3.78 (m, 2H),2.28-2.23 (m, 2H).

Example 110:3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)-1-(3-pyridyl)pyrazole-4-carboxamide

3-(4-Bromophenyl)-5-(methylamino)-1-(3-pyridyl)pyrazole-4-carbonitrile

A solution of5-amino-3-(4-bromophenyl)-1-(3-pyridyl)pyrazole-4-carbonitrile (0.53mmol) in MeOH (8 mL), paraformaldehyde (1.59 mmol) and sodium methoxide(3.17 mmol) was heated at 70° C. for 1 h. Then, it was cooled back downto RT. Sodium borohydride (5.29 mmol) was added and the reaction mixturewas stirred at RT for 16 h. It was then carefully quenched with waterand the aqueous layer was extracted with chloroform (3×20 mL). Thecombined organic layers were filtered over a hydrophobic frit andconcentrated under reduced pressure. Purification gave the titledcompound (0.56 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic):1.71 min, m/z 355.9 [M+2]⁺

N-[[4-[4-Cyano-5-(methylamino)-1-(3-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,3-(4-bromophenyl)-5-(methylamino)-1-(3-pyridyl)pyrazole-4-carbonitrile(0.56 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.62 mmol) gave,after purification, the titled compound (0.08 mmol) as an off-whitesolid. LC-MS (ES⁺, Short acidic): 4.71 min, m/z 439.2 [M+H]⁺

3-[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)-1-(3-pyridyl)pyrazole-4-carboxamide

General procedure L,N-[[4-[4-cyano-5-(methylamino)-1-(3-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.11 mmol) gave, after purification, the titled compound (0.05 mmol) asan off-white solid. UPLC-MS (ES⁻, Short acidic): 1.32 min, m/z 455.0[M−H]⁻. UPLC-MS (ES⁺, Long acidic): 2.98 min, m/z 457.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.84-8.83 (m, 1H), 8.75 (t, J=6.2 Hz, 1H), 8.63(dd, J=4.8, 1.5 Hz, 1H), 8.05-8.02 (m, 1H), 7.76 (dd, J=7.7, 1.7 Hz,1H), 7.62-7.56 (m, 3H), 7.51-7.46 (m, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.1(d, J=7.8 Hz, 1H), 7.04 (td, J=7.5, 1.7 Hz, 1H), 6.60 (br s, 1H), 4.56(d, J=6.1 Hz, 2H), 3.90 (s, 3H), 2.58 (s, 3H).

Example 111:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carboxamide

tert-ButylN-[[2-(trifluoromethyl)tetrahydropyran-4-ylidene]amino]carbamate

A solution of 2-(trifluoromethyl)oxan-4-one (1.51 mmol) in MeOH (15 mL)and tert-butyl carbazate (1.59 mmol) was stirred for 14 h at RT. Thereaction mixture was then quenched with a saturated aqueous solution ofNH₄Cl and extracted with DCM (×3). The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure. Further purification gave the titled compound (1.29 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.50 min, m/z 283.0 [M+H]⁺

tert-Butyl N-[[2-(trifluoromethyl)tetrahydropyran-4-yl]amino]carbamate

To a solution of tert-butylN-[[2-(trifluoromethyl)tetrahydropyran-4-ylidene]amino]carbamate (1.25mmol) in THF (6 mL) was added a borane tetrahydrofuran complex solution(1.0 M in THF, 2.5 mmol) at 0° C. Afterwards, the reaction mixture wasstirred for 14 h at RT. Subsequently, the reaction mixture was quenchedwith MeOH (2 mL). Then water was added and the aqueous phase wasextracted with DCM (×3). The combined organic phases were dried oversodium sulfate, filtered and concentrated under reduced pressure to givethe titled compound (1.17 mmol) as a yellow oil. UPLC-MS (ES⁺, Shortacidic): 1.50 min, m/z 301.0 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carbonitrile

A hydrogen chloride solution (4 M in dioxane, 14.5 mmol) was added totert-butyl N-[[2-(trifluoromethyl)tetrahydropyran-4-yl]amino]carbamate(1.45 mmol). Afterwards, the mixture was stirred for 15 h at RT. Aprecipitate was formed and was collected. The filtrate was concentratedunder reduced pressure to give crude[2-(trifluoromethyl)tetrahydropyran-4-yl]hydrazine hydrochloride (250mg, 1.13 mmol, 79%) as a dark orange gum. Then following generalprocedure H at 85° C.,[2-(trifluoromethyl)tetrahydropyran-4-yl]hydrazine hydrochloride (1.13mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57mmol) gave, after purification, the titled compound (0.19 mmol) as anorange gum. UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 416.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carbonitrile(0.18 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.27 mmol) gave,after purification, the titled compound (0.09 mmol) as an orange gum.UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 500.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(58 mg, 0.12 mmol) gave, after purification, the titled compound (0.02mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 518.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.60 min, m/z 518.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 7.76 (dd, J=7.7, 1.8 Hz,1H), 7.51-7.41 (m, 5H), 7.17-7.15 (m, 1H), 7.06-7.04 (m, 1H), 6.41 (s,2H), 4.55 (d, J=6.1 Hz, 2H), 4.54-4.48 (m, 1H), 4.18-4.13 (m, 2H), 3.91(s, 3H), 3.67-3.60 (m, 1H), 2.08-1.85 (m, 4H)

Example 112:5-(difluoromethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

Ethyl3-bromo-5-(difluoromethyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxylate

Diisopropyl azodicarboxylate (1.12 mmol) was added to a solution of(A)-(−)-3-hydroxytetrahydrofuran (1.12 mmol), triphenylphosphine (1.12mmol) and ethyl 3-bromo-5-(difluoromethyl)-1H-pyrazole-4-carboxylate(0.74 mmol) in THF (3.5 mL). The mixture was stirred for 1 h at RT andthen concentrated under reduced pressure. Further purification gave(isomer 2). UPLC-MS (ES⁺, Short acidic: isomer 1): 1.73 min, m/z 340.9[M+2]⁺. UPLC-MS (ES⁺, Short acidic: isomer 2): 1.63 min, m/z 340.9[M+2]⁺

3-Bromo-5-(difluoromethyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxylicacid

Sodium hydroxide (1 M in water, 0.95 mmol) was added to a solution ofethyl3-bromo-5-(difluoromethyl)-1-[(3S′)-tetrahydrofuran-3-yl]pyrazole-4-carboxylate(0.32 mmol) in THF (1.3 mL). The mixture was then heated to 50° C. for16 h, cooled to RT, acidified to ˜pH 1 with HCl (1 M in water). Thelayers were partitioned. The aqueous layer was extracted with DCM (×3).The combined organic extracts were filtered over a hydrophobic frit andconcentrated under reduced pressure to afford crude the titled compound(0.32 mmol) as an off-white solid which was used directly in the nextstep. UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 312.8 [M+2]⁺

3-Bromo-5-(difluoromethyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

A drop of DMF was added to a solution of oxalyl chloride (0.48 mmol) and3-bromo-5-(difluoromethyl)-1-[(3S′)-tetrahydrofuran-3-yl]pyrazole-4-carboxylicacid (0.32 mmol) in DCM (3 mL) at RT. The mixture was allowed to stir atRT for 1 h, cooled to 0° C. and then ammonium hydroxide (28 wt % inwater, 1.90 mmol) was added carefully. The reaction mixture was allowedto stir at RT for 10 min. The mixture was diluted with water and DCM andthe layers were partitioned. The aqueous layer was extracted with DCM(×3) and the combined organic extracts were filtered over a hydrophobicfrit and concentrated under reduced pressure. Purification gave thetitled compound (0.27 mmol) as a white solid. UPLC-MS (ES⁺, Shortacidic): 1.18 min, m/z 311.8 [M+2]⁺

5-(Difluoromethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

General procedure C, [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronicacid (0.15 mmol) and3-bromo-5-(difluoromethyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide(0.10 mmol) gave, after purification, the titled compound (0.05 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 471.0 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.36 min, m/z 471.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-t/6, 5): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.7, 1.9 Hz, 1H),7.68-7.61 (m, 3H), 7.60 (br s, 1H), 7.52-7.45 (m, 1H), 7.40 (d, J=8.4Hz, 2H), 7.33 (t, J=53.6 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.08-7.01 (m,1H), 5.28-5.19 (m, 1H), 4.53 (d, 0.7=6.1 Hz, 2H), 4.14-4.03 (m, 2H),3.94-3.83 (m, 5H), 2.48-2.31 (m, 2H).

Example 113:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.19mmol) and5-amino-3-(4-bromophenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.14 mmol) gave, after purification, the titled compound (0.06 mmol) asa brown solid. UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 450 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.06 mmol) gave, after purification, the titled compound (0.03 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 468.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 468.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.83 (t, J=6.2 Hz, 1H), 7.51 (dd, J=9.2, 3.3 Hz, 1H), 7.45(d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.34 (m, 1H), 7.19 (m, 1H),6.42 (s, 2H), 4.55 (d, J=6.1 Hz, 2H), 4.30-4.19 (m, 1H), 3.90 (s, 3H),3.88-3.80 (m, 2H), 3.54 (t, J=10.5 Hz, 1H), 3.36-3.26 (m, 1H), 2.06-1.95(m, 2H), 1.79-1.59 (m, 2H).

Example 114:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol), andtetrahydrofuran-3-ylhydrazine hydrochloride (0.68 mmol) gave, afterpurification, the titled compound (0.40 mmol) as an off-white solid.UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 334.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.23mmol) and5-amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.18 mmol) gave, after purification, the titled compound (0.09 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 436[M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.09 mmol) gave, after purification, the titled compound (0.07 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 454.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.06 min, m/z 454.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.84 (t, J=6.0 Hz, 1H), 7.52 (dd, J=9.2, 3.3 Hz, 1H), 7.46(d, J=8.2 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.38-7.30 (m, 1H), 7.19 (dd,J=9.1, 4.3 Hz, 1H), 6.40 (s, 2H), 4.99-4.89 (m, 1H), 4.55 (d, J=6.0 Hz,2H), 4.03-3.92 (m, 2H), 3.90 (s, 3H), 3.85-3.76 (m, 2H), 2.30-2.21 (m,2H).

Example 115:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (1.39 g, 5.29mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.00 g, 6.35mmol) gave, after purification, the titled compound (4.78 mmol) as anoff-white solid. LC-MS (ES⁺, Short acidic): 5.64 min, m/z 347.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(4.78 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (9.56mmol) gave, after purification, the titled compound (1.98 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 450.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(1.98 mmol) gave, after purification, the titled compound carboxamide(1.46 mmol) as a beige solid. UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z468.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 468.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.1 Hz, 1H), 7.52 (dd, J=9.2, 3.3Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.38-7.30 (m,1H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 6.38 (s, 2H), 4.55 (d, J=6.1 Hz, 2H),4.42-4.27 (m, 1H), 4.01-3.93 (m, 2H), 3.90 (s, 3H), 3.48-3.37 (m, 2H),2.05-1.91 (m, 2H), 1.82-1.72 (m, 2H).

Example116:5-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.88mmol), and tetrahydropyran-4-ylhydrazine hydrochloride (1.05 mmol) gave,after purification, the titled compound (0.60 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 366.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.60 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.27 mmol) gave,after purification, the titled compound (0.49 mmol) as a brown solid.UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 450.1 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.26 mol) gave, after purification, the titled compound (0.10 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 468.0[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.08 min, m/z 468.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □): 8.72 (t, J=5.9 Hz, 1H), 7.75 (dd, J=7.6, 1.6 Hz,1H), 7.51-7.42 (m, 2H), 7.34-7.23 (m, 2H), 7.16 (d, J=8.3 Hz, 1H),7.06-7.02 (m, 1H), 6.32 (s, 2H), 4.57 (d, J=6.1 Hz, 2H), 4.40-4.33 (m,1H), 3.99-3.95 (m, 2H), 3.91 (s, 3H), 3.46-3.39 (m, 2H), 2.03-1.93 (m,2H), 1.79-1.75 (m, 2H).

Example 117:5-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

General K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.20 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.43 mmol) gave,after purification, the titled compound (0.16 mmol) as a brown solid.UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 450.0 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.16 mmol) gave, after purification, the titled compound (0.09 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 468.0[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 468.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, □): 8.72 (t, J=5.9 Hz, 1H), 7.75 (dd, J=7.5, 1.8 Hz,1H), 7.51-7.41 (m, 2H), 7.33-7.26 (m, 2H), 7.16 (d, J=8.2 Hz, 1H),7.06-7.02 (m, 1H), 6.35 (s, 2H), 4.57 (d, J=6.0 Hz, 2H), 4.30-4.22 (m,1H), 3.91 (s, 3H), 3.89-3.83 (m, 2H), 3.54 (t, J=10.5 Hz, 1H), 3.39-3.26(m, 1H), 2.03-1.98 (m, 2H), 1.77-1.65 (m, 2H).

Example 118:5-amino-1-cyclopentyl-3-[4-fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[(5-Bromo-2-fluoro-phenyl)methyl]-2-methoxy-benzamide

To a solution of 5-bromo-2-fluorobenzonitrile (2.50 mmol) in THF (15mL), cooled at 0° C., was added dropwise a borane tetrahydrofurancomplex solution (1 M in THF, 7.5 mL, 7.50 mmol). The reaction wasstirred at 0° C. for 20 min and then at RT for 16 h. The reactionmixture was quenched with MeOH dropwise (15 mL) and the solution wasconcentrated under reduced pressure. The oil was then partitionedbetween an aqueous solution of NaOH (1 M) and EtOAc. The organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give crude(5-bromo-2-fluoro-phenyl)methanamine (629 mg) as a colourless oil. Theoil was taken up with THF (10 mL) and cooled to 0° C. 2-Methoxybenzoylchloride (2.75 mmol) and N,N-diisopropylethylamine (7.50 mmol) were thenadded sequentially. The reaction mixture was stirred for 20 min at 0° C.and then allowed to stir at RT for 16 h. The mixture was quenched with asaturated aqueous solution of NH₄Cl and the organics were removed underreduced pressure. The residue was then extracted with EtOAc. The organiclayer was washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was then purified togive the titled compound (1.30 mmol) as a colourless oil. UPLC-MS (ES⁺,Short acidic): 1.75 min, m/z 339.9 [M+2]⁺

N-[[2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure R,N-[(5-bromo-2-fluoro-phenyl)methyl]-2-methoxy-benzamide (1.30 mmol)gave, after purification, the titled compound (1.26 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.92 min, m/z 386.0 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure D,N-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide(0.65 mmol) and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide(0.62 mmol) gave, after purification, the titled compound (0.05 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 452.1.0[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.59 min, m/z 452.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.71 (t, J=5.9 Hz, 1H), 7.69 (dd, J=7.6, 1.8 Hz,1H), 7.52 (dd, J=7.5, 2.1 Hz, 1H), 7.46-7.44 (m, 1H), 7.42-7.36 (m, 1H),7.26 (dd, J=10.0, 8.5 Hz, 1H), 7.15-7.11 (m, 1H), 7.04-6.99 (m, 1H),6.31 (s, 2H), 4.64-4.54 (m, 3H), 3.84 (s, 3H), 1.98-1.90 (m, 2H),1.90-1.81 (m, 2H), 1.81-1.69 (m, 2H), 1.61-1.50 (m, 2H).

Example 119:5-amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (150 mg,0.53 mmol), and tetrahydrofuran-3-ylhydrazine hydrochloride (0.64 mmol)gave, after purification, the titled compound (0.53 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): E72 min, m/z 352.8 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(0.23 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.32mmol) gave, after purification, the titled compound (0.20 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): E59 min, m/z 454.0 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.20 mmol) gave, after purification, the titled compound (0.16 mmol) asa beige solid. UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 494.0 [M+Na]⁺.UPLC-MS (ES⁺, Long acidic): 3.20 min, m/z 472.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.82 (t, J=6.1 Hz, 1H), 7.50 (dd, J=9.2, 3.3 Hz, 1H), 7.43(t, J=8.0 Hz, 1H), 7.37-7.28 (m, 3H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 6.34(s, 2H), 4.97-4.91 (m, 1H), 4.56 (d, J=5.9 Hz, 2H), 4.01-3.93 (m, 2H),3.90 (s, 3H), 3.83-3.78 (m, 2H), 2.28-2.23 (m, 2H).

Example 120:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

N-[(2,2,2-Trifluoro-1-methyl-ethylidene)amino]benzamide

General procedure S, benzhydrazide (49.9 mmol) and1,1,1-trifluoroacetone (74.9 mmol) gave, after washing, the titledcompound as a white solid. UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z230.9 [M+H]⁺

N′-(2,2,2-Trifluoro-1-methyl-ethyl)benzohydrazide

To a solution of N-[(2,2,2-trifluoro-1-methyl-ethylidene)amino]benzamide(21.7 mmol) in THF (50 mL), cooled at 0° C., was added dropwise boranetetrahydrofuran complex solution (1 M in THF, 43.44 mmol). The reactionwas allowed to return to RT and stirred for 14 h. The reaction wascooled to 0° C., quenched with MeOH (20 mL) and then allowed to returnto RT. The mixture was evaporated and DCM (75 mL) was added. The slurrywas filtered to remove insoluble material. The organic layer was washedwith saturated ammonium chloride (50 mL), dried over magnesium sulfate,filtered and concentrated under reduced pressure. Pet. Ether (50 mL) wasadded to the yellow oil resulting in a solid crashing out. The solventwas reduced by 50% and the slurry cooled in an ice bath and filtered.The solid was washed with Pet. Ether (25 mL) to give the titled compoundas a white solid. UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 232.9[M+H]⁺

(2,2,2-Trifluoro-1-methyl-ethyl)hydrazine hydrochloride

Following general procedure U,N′-(2,2,2-trifluoro-1-methyl-ethyl)benzohydrazide (4.0 g, 17.2 mmol),gave (2,2,2-trifluoro-1-methyl-ethyl)hydrazine hydrochloride (1.7 g,10.3 mmol, 60% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆, δ): 9.65(br s, 2H), 5.97 (br s, 1H), 3.87-3.80 (m, 1H), 1.28 (d, J=6.8 Hz, 3H).

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

To a solution of 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(7.98 mmol) in EtOH (50 mL) was added triethylamine (31.9 mmol). After10 min stirring, (2,2,2-trifluoro-1-methyl-ethyl)hydrazine hydrochloride(12.0 mmol) was added. The reaction mixture was heated to 80° C. for 14h, cooled and concentrated under reduced pressure. Further purificationgave the titled compound (7.24 mmol) as an off-white solid. UPLC-MS(ES⁺, Short acidic): 1.91 min, m/z 360.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (4.26mmol), and5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(2.51 mmol) gave, after purification, the titled compound (2.17 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.71 min, 462.0 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.83 mmol) gave, after purification, the titled compound (0.42 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 480.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.57 min, m/z 480.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.84 (t, J=6.1 Hz, 1H), 7.52 (dd, J=9.2, 3.3 Hz, 1H),7.48-7.41 (m, 4H), 7.37-7.32 (m, 1H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 6.67(s, 2H), 5.35-5.24 (m, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 1.62(d, J=6.9 Hz, 3H).

Example 121:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(0.92 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.39 mmol) gave,after purification, the titled compound (0.41 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 444.0 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.40 mmol) gave, after purification, the titled compound (0.182 mmol)as a white solid. UPLC-MS (ES⁺, Short acidic): 1.48 min, m/z 462.0[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.42 min, m/z 461.9 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.2 Hz, 1H), 7.76 (dd, J=7.6, 1.8 Hz,1H), 7.51-7.42 (m, 5H), 7.16 (d, J=7.8 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz,1H), 6.67 (br s, 2H), 5.33-5.26 (m, 1H), 4.56 (d, J=6.1 Hz, 2H), 3.90(s, 3H), 1.62 (d, J=6.8 Hz, 3H).

Example 122:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile

A solution of triethylamine (380.13 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (25.0 g, 95.03mmol) in EtOH (600 mL) was left to stir for 10 min before adding2,2,2-trifluoroethyl hydrazine (70 wt % in water, 142.54 mmol) in onealiquot to almost immediately give a clear orange solution and anexotherm from 22-29° C. over 2-3 min. The resulting mixture was thenheated to reflux for 5 h. Once the reaction has reached completion, thereaction mixture was concentrated under reduced pressure to give anorange solid. Further purification gave the titled compound (25.3 g,73.31 mmol, 77% yield) as a pale yellow solid. UPLC-MS (ES⁺, Shortacidic): 1.78 min, m/z 346.8 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

A mixture of5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(29.0 mmol), potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (58.03mmol), cesium carbonate (86.92 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2.03 mmol), THF(120 mL) and water (60 mL) at RT was degassed under vacuum and flushedwith nitrogen three times. Then palladium (II) acetate (1.01 mmol) wasadded and the mixture was degassed again. The reaction mixture washeated to reflux for 2 h, cooled and diluted with water (100 mL) andEtOAc (200 mL), filtered over Celite® and separated. The aqueous layerwas extracted with EtOAc (100 mL) and the combined organic extracts werewashed with water before drying over magnesium sulfate. Furtherpurification gave a solid which was further purified using a formationof a slurry in hot THF and EtOAc (100 mL, 1:1) and precipitated withPet. Ether and stirred until cold. The product was filtered off andwashed with Pet. Ether to give the titled compound (24.7 mmol). UPLC-MS(ES⁺, Short acidic): 1.61 min, m/z 448.0 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(30.40 mmol) was added a solution of sulfuric acid (304 mmol) and TFA(912 mmol) to give a light brown solution. The reaction mixture washeated to 58° C. for 5 h, cooled and slowly poured onto an ice-cooledsolution of sodium bicarbonate (153.2 g, 1824 mmol) in water (750 mL)and then extracted with EtOAc (3×250 ml). The combined organic extractswere washed with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Further purification gave thetitled compound (28.4 mmol). UPLC-MS (ES⁻, Short acidic): 1.44 min, m/z463.7 [M−H]⁻ UPLC-MS (ES⁺, Long acidic): 3.31 min, m/z 465.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆, δ): 8.85 (t, J=6.0 Hz, 1H), 7.52 (dd, J=9.2, 3.3Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.38-7.32 (m,1H), 7.19 (dd, J=9.2, 4.3 Hz, 1H), 6.68 (s, 2H), 4.94 (q, J=9.0 Hz, 2H),4.56 (d, J=6.1 Hz, 2H), 3.90 (s, 3H).

Example 123:5-amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzaimde

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.22 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.31mmol) gave, after purification, the titled compound (0.22 mmol, assumedquantitative yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.61min, m/z 468.0 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.22 mmol) gave, after purification, the titled compound (0.15 mmol) asa beige solid. UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 507.9 [M+Na]⁺.UPLC-MS (ES⁺, Long acidic): 3.20 min, m/z 486.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.81 (t, J=6.1 Hz, 1H), 7.51 (dd, J=9.3, 3.4 Hz, 1H),7.46-7.39 (m, 1H), 7.37-7.27 (m, 3H), 7.19 (dd, J=9.2, 4.3 Hz, 1H), 6.32(s, 2H), 4.57 (d, J=5.9 Hz, 2H), 4.40-4.32 (m, 1H), 3.96 (dd, J=11.5,3.4 Hz, 2H), 3.90 (s, 3H), 3.47-3.37 (m, 2H), 2.03-1.96 (m, 2H),1.79-1.75 (m, 2H).

Example 124:5-amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile

General procedure H,2-[(4-bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.73mmol) and 2,2,2-trifluoroethyl hydrazine (70 wt % in water, 0.87 mmol)gave, after purification, the titled compound (0.47 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 362.8 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(0.23 mmol), and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.34 mmol) gave,after purification, the titled compound (0.21 mmol) as a yellow solid.UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 448.0 [M+H]⁺

5-Amino-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

Following general procedure L,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.21 mmol) gave, after purification, the titled compound (0.15 mmol) asa beige solid. UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 488.0 [M+Na]⁺.UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 466.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.79 (t, J=6.1 Hz, 1H), 7.73 (dd, J=7.5, 1.8 Hz, 1H),7.50-7.46 (m, 1H), 7.45-7.38 (m, 1H), 7.27-7.24 (m, 2H), 7.16 (d, J=8.1Hz, 1H), 7.06-7.02 (m, 1H), 6.64 (s, 2H), 4.99-4.93 (m, 2H), 4.56 (d,J=5.9 Hz, 2H), 3.91 (s, 3H).

Example125:5-amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(0.23 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.33mmol) gave, after purification, the titled compound (0.20 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 466.1 [M+H]⁺

5-Amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.20 mmol) gave, after purification, the titled compound (0.12 mmol) asa beige solid. UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 506.0 [M+Na]⁺.UPLC-MS (ES⁺, Long acidic): 3.34 min, m/z 484.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, □): 8.89 (t, J=6.1 Hz, 1H), 7.50 (dd, J=9.2, 3.5 Hz, 1H),7.45-7.38 (m, 1H), 7.37-7.32 (m, 1H), 7.25 (d, J=9.2 Hz, 2H), 7.19 (dd,J=9.1, 4.2 Hz, 1H), 6.64 (s, 2H), 4.99-4.93 (m, 2H), 4.56 (d, J=6.1 Hz,2H), 3.90 (s, 3H).

Example 126:5-amino-1-(2,2-difluoro-1-methyl-ethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(2,2-difluoro-1-methyl-ethylidene)amino]carbamate

A modified general procedure E at 60° C., tert-butyl carbazate (1.51mmol) and 1,1-difluoro-propan-2-one (1.82 mmol) gave crude the titledcompound (1.51 mmol) as a white solid. UPLC-MS (ES⁻, Short acidic): 1.45min, m/z 206.8 [M−H]⁻

5-Amino-3-(4-bromophenyl)-1-(2,2-difluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

General procedure O at RT, tert-butylN-[(2,2-difluoro-1-methyl-ethylidene)amino]carbamate (0.58 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.46 mmol) gave,after purification, the titled compound (0.43 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 340.6 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2-difluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(2,2-difluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(0.15 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.22 mmol) gave,after purification, the titled compound (0.08 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 426.0 [M+H]⁺

5-Amino-1-(2,2-difluoro-1-methyl-ethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2,2-difluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.08 mmol) gave, after purification, the titled compound (0.04 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 444.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.25 min, m/z 444.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.74 (dd, J=7.6, 1.8 Hz, 1H),7.51-7.38 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.07-7.00 (m, 1H), 6.53 (s,2H), 6.21 (dt, J=55.7, 5.3 Hz, 1H), 4.85-4.70 (m, 1H), 4.54 (d, J=6.2Hz, 2H), 3.89 (s, 3H), 1.44 (d, J=6.7 Hz, 3H).

Example 127:5-amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

General procedure H, tetrahydropyran-3-ylhydrazine hydrochloride (0.77mmol) and2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.64mmol) gave, after purification, the titled compound (0.20 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 366.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.18 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (106 mg,0.37 mmol) gave, after purification, the titled compound (54 mg, 0.12mmol, 66% yield) as a brown solid. UPLC-MS (ES⁺, Short acidic): 1.68min, m/z 468.0 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(54 mg, 0.12 mmol) gave, after purification, the titled compound (20 mg,0.04 mmol, 36% yield) as an off-white solid. UPLC-MS (ES⁺, Shortacidic): 1.47 min, m/z 485.9 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.37min, m/z 486.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.81 (t, J=6.0 Hz,1H), 7.50 (dd, J=9.2, 3.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.37-7.26 (m, 3H),7.19 (dd, J=9.3, 4.3 Hz, 1H), 6.35 (s, 2H), 4.56 (d, J=6.0 Hz, 2H),4.30-4.22 (m, 1H), 3.90 (s, 3H), 3.87-3.82 (m, 2H), 3.58-3.48 (m, 1H),3.37-3.27 (m, 1H), 2.03-1.98 (m, 2H), 1.77-1.65 (m, 2H).

Example 128:5-amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (500 mg,1.78 mmol) and 2,2,2-trifluoroethyl hydrazine (70 wt % in water, 31 μL,2.13 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(132 mg, 0.36 mmol, 20% yield) as a brown solid. UPLC-MS (ES⁺, Shortacidic): 1.82 min, m/z 362.7 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(0.18 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.27mmol) gave, after purification, the titled compound (0.12 mmol) as apale orange solid. UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 465.9[M+H]⁺.

5-Amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.12 mmol) gave, after purification, the titled compound (22 mg, 0.05mmol, 39% yield) as a light brown solid. UPLC-MS (ES⁺, Short acidic):1.50 min, m/z 484.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.44 min, m/z484.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (t, J=5.9 Hz, 1H), 7.51(dd, J=9.7, 3.7 Hz, 1H), 7.47-7.40 (m, 1H), 7.37-7.27 (m, 3H), 7.19 (dd,J=9.1, 4.3 Hz, 1H), 6.63 (s, 2H), 4.95 (q, J=9.3 Hz, 2H), 4.57 (d, J=6.5Hz, 2H), 3.90 (s, 3H).

Example 129:5-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(0.18 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.27 mmol) gave,after purification, the titled compound (0.07 mmol) as a pale brownsolid. UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 448.0 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(27 mg, 0.06 mmol) gave, after purification, the titled compound (0.03mmol, 54% yield) as a light brown solid. UPLC-MS (ES⁺, Short acidic):1.45 min, m/z 466.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.32 min, m/z466.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.75(dd, J=7.7, 1.8 Hz, 1H), 7.51-7.42 (m, 2H), 7.35-7.28 (m, 2H), 7.16 (d,J=7.7 Hz, 1H), 7.07-7.01 (m, 1H), 6.61 (s, 2H), 5.00-4.90 (m, 2H), 4.57(d, J=6.0 Hz, 2H), 3.90 (s, 3H).

Example 130:5-amino-1-cyclopentyl-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2-fluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile (0.71mmol) and cyclopentylhydrazine hydrochloride (0.85 mmol) afforded, afterpurification, the titled compound (0.37 mmol) as a yellow gum. UPLC-MS(ES⁺, Short acidic): 1.95 min, m/z 350.8 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.37 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.41 mmol)afforded, after purification, the titled compound (0.32 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 434.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[2-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-2-methoxy-benzamide(0.32 mmol) afforded, after purification, the titled compound (0.07mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 452.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.52 min, m/z 452.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.79 (t, J=6.0 Hz, 1H), 7.74 (dd, J=7.7, 1.8 Hz,1H), 7.52-7.46 (m, 1H), 7.43-7.37 (m, 1H), 7.26-7.21 (m, 2H), 7.19-7.14(m, 1H), 7.04 (td, J=11.2, 0.9 Hz, 1H), 6.29 (s, 2H), 4.66-4.59 (m, 1H),4.56 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 2.02-1.73 (m, 6H), 1.64-1.56 (m,2H).

Example 131:5-amino-1-(1-cyclopropylethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[1-cyclopropylethylideneamino]carbamate

Following general procedure E, cyclopropyl methyl ketone (0.60 mL, 6.06mmol), and tert-butyl carbazate (880 mg, 6.66 mmol) gave the titledcompound (6.06 mmol) as a white solid. ¹H NMR (400 MHz, CDCl₃, □): 7.35(br s, 1H), 1.80-1.71 (m, 1H), 1.63 (s, 3H), 1.50 (s, 9H), 0.77 (s, 2H),0.75 (s, 2H).

5-Amino-3-(4-bromophenyl)-1-(T-cyclopropylethyl)pyrazole-4-carbonitrile

To a solution of tert-butyl N-[1-cyclopropylethylideneamino]carbamate(6.05 mmol) in THF (20 mL) was added a borane dimethyl sulfide complexsolution (2 M in THF, 10.3 mmol). The reaction was stirred at RT for 2 hand then the volatiles were removed under reduced pressure. The residuewas taken up with MeOH (20 mL) and concentrated hydrochloric acid (30.3mmol) was added. Then the reaction mixture was stirred at RT for 16 hand concentrated under reduced pressure. The residue was taken up withEtOH (10 mL) followed by addition of2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (100 mg, 0.38mmol) and triethylamine (1.9 mmol). The reaction mixture was heated toreflux and stirred for 16 h. All volatiles were then removed underreduced pressure and the residue was purified to give the titledcompound (0.33 mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic):1.95 min, m/z 332.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-n-cyclopropylethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(1-cyclopropylethyl)pyrazole-4-carbonitrile(0.33 mmol), and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.48 mmol) gave,after purification, the titled compound (0.12 mmol) as a yellow solid.UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z 416.1 [M+H]⁺

5-Amino-1-(T-cyclopropylethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L, N-[[4-[5-amino-4-cyano-1-(1-cyclopropylethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.12 mmol) gave,after purification, the titled compound (0.06 mmol) as a solid. UPLC-MS(ES⁺, Short acidic): 1.47 min, m/z 434.1 [M+H]⁺. UPLC-MS (ES⁺, Longacidic): 3.35 min, m/z 434.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, □): 8.73(t, J=6.4 Hz, 1H), 7.75 (dd, J=7.7, 1.7 Hz, 1H), 7.50-7.40 (m, 5H), 7.15(d, J=8.2 Hz, 1H), 7.06-7.02 (m, 1H), 6.26 (s, 2H), 4.54 (d, J=6.2 Hz,2H), 3.90 (s, 3H), 3.71-3.64 (m, 1H), 1.41 (d, J=6.6 Hz, 3H), 1.33-1.23(m, 1H), 0.58-0.51 (m, 1H), 0.40-0.34 (m, 2H), 0.28-0.22 (m, 1H).

Example 132:5-amino-3-[3,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-3,5-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

Following a modified general procedure H at RT,2-[(4-chloro-3,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(0.98 mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (1.18 mmol)gave crude the titled compound (0.98 mmol). UPLC-MS (ES⁺, Short acidic):1.82 min, m/z 339.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.09 mmol) and5-amino-3-(4-chloro-3,5-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.49 mmol) gave, after purification, the titled compound (0.13 mmol).UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 468.1 [M+H]⁺

5-Amino-3-[3,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

Following general method L,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide(0.13 mmol) gave, after purification, the titled compound (0.01 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 486.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.18 min, m/z 486.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.57 (t, J=5.5 Hz, 1H), 7.73 (dd, J=7.8, 1.8 Hz, 1H),7.51-7.44 (m, 1H), 7.26-7.19 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.05-7.01(m, 1H), 6.27 (br s, 2H), 4.58 (d, J=5.6 Hz, 2H), 4.43-4.32 (m, 1H),4.00-3.93 (m, 2H), 3.88 (s, 3H), 3.43 (t, J=11.9 Hz, 2H), 2.04-1.94 (m,2H), 1.79-1.75 (m, 2H).

Example 133:5-amino-3-[3,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzaimde

General procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.99mmol) and5-amino-3-(4-chloro-3,5-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.49 mmol) gave crude the titled compound (0.49 mmol). UPLC-MS (ES⁺,Short acidic): 1.67 min, m/z 486.0 [M+H]⁺

5-Amino-3-[3,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.49 mmol) gave, after purification, the titled compound (0.09 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 504.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.31 min, m/z 504.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.67 (t, J=5.6 Hz, 1H), 7.48 (dd, J=9.0, 3.3 Hz, 1H),7.36-7.30 (m, 1H), 7.26-7.13 (m, 3H), 6.27 (br s, 2H), 4.58 (d, J=5.5Hz, 2H), 4.43-4.33 (m, 1H), 3.99-3.94 (m, 2H), 3.87 (s, 3H), 3.43 (t,J=11.1 Hz, 2H), 2.03-1.93 (m, 2H), 1.79-1.74 (m, 2H).

Example 134:5-amino-1-cyclopentyl-3-[6-[[(2-methoxybenzoyl)amino]methyl]-3-pyridyl]pyrazole-4-carboxamide

N-[(5-Bromo-2-pyridyl)methyl]-2-methoxy-benzamide

To a solution of (5-bromo-2-pyridyl)methanamine (1.60 mmol) in DMF (4mL), at 0° C., was added N,N-diisopropylethylamine (4.81 mmol). After 10min of stirring, 2-methoxybenzoyl chloride (3.21 mmol) was added slowly.The reaction mixture was warmed to RT and stirred under nitrogen for 18h. The mixture was quenched with saturated aqueous sodium bicarbonatesolution and diluted with EtOAc. The layers were partitioned and theaqueous layer was extracted with EtOAc. The combined organic extractswere washed with brine, dried over sodium sulfate and concentrated underreduced pressure. Further purification gave the titled compound (0.92mmol) as a pale yellow oil. UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z322.8 [M+2]⁺

[6-[[(2-Methoxybenzoyl)amino]methyl]-3-pyridyl]boronic acid

To a solution of N-[(5-bromo-2-pyridyl)methyl]-2-methoxy-benzamide (240mg, 0.75 mmol) in THF (10 mL), at −78° C., was slowly addedtriisopropylborate (0.35 mL, 1.50 mmol). A solution of n-butyllithium(2.5 M in hexane, 0.90 mL, 2.24 mmol) was added dropwise and the mixturewas stirred at −78° C. for 1 h, and then allowed to return to −20° C.for 1.5 h. The reaction mixture was quenched with hydrochloric acid (2M), neutralized with saturated aqueous sodium bicarbonate solution andpartitioned with EtOAc. The aqueous layer was extracted with EtOAc. Thecombined organic extracts were filtered over a hydrophobic frit andconcentrated under reduced pressure to give the titled compound (0.86mmol), which was used as such in the next step. UPLC-MS (ES⁺, Shortacidic): 0.99 min, m/z 287.0 [M+H]⁺

5-Amino-1-cyclopentyl-3-[6-[[(2-methoxybenzoyl)amino]methyl]-3-pyridyl]pyrazole-4-carboxamide

Following general procedure D,[6-[[(2-methoxybenzoyl)amino]methyl]-3-pyridyl]boronic acid (0.86 mmol)and 5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (0.43 mmol)gave, after purification, the titled compound (0.09 mmol) as a lightbrown solid. UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 435.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.07 min, m/z 435.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.99 (t, J=6.1 Hz, 1H), 8.64 (m, 1H), 7.88 (dd, J=8.1, 2.2Hz, 1H), 7.84 (dd, J=7.7, 1.8 Hz, 1H), 7.50-7.47 (m, 1H), 7.42 (d, J=8.5Hz, 1H), 7.18 (dd, J=8.6, 0.9 Hz, 1H), 7.01 (td, J=7.6, 1.2 Hz, 1H),6.23 (s, 2H), 4.68-4.59 (m, 3H), 3.95 (s, 3H), 2.02-1.86 (m, 4H),1.85-1.76 (m, 2H), 1.65-1.55 (m, 2H).

Example 135:5-amino-1-(2-hydroxy-1-methyl-ethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl N-[(2-hydroxy-1-methyl-ethylidene)amino]carbamate

General procedure E, tert-butyl carbazate (7.57 mmol) and hydroxyacetone(9.08 mmol) gave the titled compound (7.57 mmol) as a yellow oil.UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 188.9 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-(2-hydroxy-1-methyl-ethyl)pyrazole-4-carbonitrile

General procedure O, tert-butylN-[(2-hydroxy-1-methyl-ethylidene)amino]carbamate (7.39 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol), gaveafter purification, the titled compound (0.28 mmol) as an off-whitesolid. UPLC (ES⁺, Short acidic): 1.59 min, 322.9 m/z [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2-hydroxy-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.72 mmol), and5-amino-3-(4-bromophenyl)-1-(2-hydroxy-1-methyl-ethyl)pyrazole-4-carbonitrile(0.28 mmol) gave, after purification, the titled compound (0.22 mmol) asan orange solid.

UPLC-MS (ES⁺, Short acidic): 1.42 min, 406.1 m/z [M+H]⁺

5-Amino-1-(2-hydroxy-1-methyl-ethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2-hydroxy-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.22 mmol) gave, after purification, the titled compound (0.07 mmol) asa pale brown solid. UPLC-MS (ES⁺, Short acidic): 1.25 min, 424.1 m/z[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.78 min, 424.1 m/z [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.6, 1.7 Hz,1H), 7.50-7.40 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 7.06-7.02 (m, 1H), 6.24(s, 2H), 4.89 (t, J=5.4 Hz, 1H), 4.55 (d, J=5.9 Hz, 2H), 4.36-4.27 (m,1H), 3.90 (s, 3H), 3.70-3.62 (m, 2H), 1.29 (d, J=6.7 Hz, 3H).

Example 136:5-amino-1-cyclopentyl-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.28 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (89 mg,0.31 mmol) afforded, after purification, the titled compound (126 mg,0.28 mmol, 99%) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.75min, m/z 452.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(133 mg, 0.29 mmol) afforded, after purification, the titled compound(66 mg, 0.14 mmol, 47% yield) as a white solid. UPLC-MS (ES⁺, Shortacidic): 1.58 min, m/z 470.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.63min, m/z 470.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.88 (t, J=6.0 Hz,1H), 7.50 (dd, J=7.6, 1.7 Hz, 1H), 7.42-7.32 (m, 2H), 7.25-7.17 (m, 3H),6.28 (s, 2H), 4.66-4.59 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.91 (s, 3H),2.03-1.73 (m, 6H), 1.63-1.53 (m, 2H).

Example 137:5-amino-1-cyclopentyl-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.39 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.58mmol) gave, after recrystallization from MeOH, the titled compound (0.23mmol). UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 470.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.22 mmol) gave, after purification, the titled compound (0.13 mmol) asa pale brown solid. UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 488.2[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.80 min, m/z 488.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.86 (t, J=6.0 Hz, 1H), 7.49 (dd, J=9.2, 3.3 Hz,1H), 7.37-7.32 (m, 1H), 7.27-7.17 (m, 3H), 6.23 (s, 2H), 4.66-4.58 (m,1H), 4.55 (d, J=6.9 Hz, 2H), 3.90 (s, 3H), 2.02-1.92 (m, 2H), 1.91-1.83(m, 2H), 1.82-1.72 (m, 2H), 1.63-1.52 (m, 2H).

Example 138:5-amino-1-cyclopentyl-3-[3,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-chloro-3,5-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

A modified general procedure H at RT, cyclopentylhydrazine hydrochloride(0.47 mmol) and2-[(4-chloro-3,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(0.39 mmol) gave, after purification, the titled compound (0.31 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 2.13 min, m/z 323.0[M]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-chloro-3,5-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.16 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.31 mmol) gave,after purification, the titled compound (0.11 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.86 min, m/z 452.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[3,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide(0.11 mmol) gave, after purification, the titled compound (0.08 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 470.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.80 min, m/z 470.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.56 (t, J=5.5 Hz, 1H), 7.73 (dd, J=7.7, 1.7 Hz, 1H),7.50-7.43 (m, 1H), 7.25-7.17 (m, 2H), 7.13 (d, J=8.3 Hz, 1H), 7.05-6.99(m, 1H), 6.20 (s, 2H), 4.68-4.54 (m, 3H), 3.87 (s, 3H), 2.05-1.73 (m,6H), 1.65-1.51 (m, 2H).

Example 139:5-amino-1-cyclopentyl-3-[3,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-chloro-3,5-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.16 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.39mmol) gave, after purification, the titled compound (20 mg, 0.04 mmol,27% yield) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.91 min,m/z 470.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[3,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.04 mmol) gave, after purification, the titled compound (0.03 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 488.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.92 min, m/z 488.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.66 (t, J=5.6 Hz, 1H), 7.47 (dd, J=9.2, 3.3 Hz, 1H),7.37-7.28 (m, 1H), 7.25-7.12 (m, 3H), 6.20 (s, 2H), 4.67-4.52 (m, 3H),3.86 (s, 3H), 2.05-1.73 (m, 6H), 1.65-1.52 (m, 2H).

Example 140:5-amino-1-cyclopentyl-3-[2,6-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2,6-difluoro-phenyl)-1H-pyrazole-4-carbonitrile

General procedure H in the absence of triethylamine, hydrazine hydrate(55-60% in water, 1.43 mmol) and2-[(4-bromo-2,6-difluoro-phenyl)-methoxy-methylene]propanedinitrile(1.19 mmol) gave crude the titled compound (1.17 mmol) as a pale yellowsolid. UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 300.8 [M+2]⁺

5-Amino-3-(4-bromo-2,6-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

Following general procedure N,5-amino-3-(4-bromo-2,6-difluoro-phenyl)-1H-pyrazole-4-carbonitrile (350mg, 1.17 mmol) and bromocyclopentane (1.76 mmol) gave, afterpurification, a mixture of5-amino-3-(4-bromo-2,6-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrileand the titled compound (3:2 ratio) (0.80 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.86 and 1.92 min, m/z 368.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-3,5-difluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K, a mixture of5-amino-3-(4-bromo-2,6-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrileand3-amino-5-(4-bromo-2,6-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(0.33 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.36 mmol) gave,after purification, the titled compound (0.12 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 452.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[2,6-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-3,5-difluoro-phenyl]methyl]-2-methoxy-benzamide(0.12 mmol) gave, after purification the titled compound (0.03 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 470.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.60 min, m/z 470.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.81 (t, J=6.2 Hz, 1H), 7.72 (dd, J=7.6, 1.9 Hz, 1H),7.52-7.45 (m, 1H), 7.17-7.13 (m, 3H), 7.06-7.00 (m, 1H), 6.28 (br s,2H), 4.67-4.60 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 2.03-1.92(m, 2H), 1.90-1.72 (m, 4H), 1.62-1.52 (m, 2H).

Example 141:5-amino-3-[2,3-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile(200 mg, 0.79 mmol) and tetrahydropyran-4-ylhydrazine hydrochloride (144mg, 0.94 mmol) gave, after purification the titled compound (0.65 mmol).UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 339.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.32 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.65 mmol) gave,after purification the titled compound (0.24 mmol) as a yellow solid.UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 468.1 [M+H]⁺

5-Amino-3-[2,3-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-2-methoxy-benzamide(112 mg, 0.24 mmol) gave, after purification the titled compound (78 mg,0.16 mmol, 67% yield) as an off-white solid. UPLC-MS (ES⁺, Shortacidic): 1.40 min, m/z 486.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.12min, m/z 486.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz,1H), 7.78-7.72 (m, 1H), 7.53-7.45 (m, 1H), 7.29-7.19 (m, 2H), 7.16 (d,J=7.8 Hz, 1H), 7.07-7.01 (m, 1H), 6.31 (s, 2H), 4.60 (d, J=6.0 Hz, 2H),4.43-4.32 (m, 1H), 4.00-3.93 (m, 2H), 3.91 (s, 3H), 3.45-3.39 (m, 2H),2.01-1.90 (m, 2H), 1.82-1.73 (m, 2H).

Example 142:5-amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(106 mg, 0.31 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (181 mg,0.63 mmol) gave, after purification the titled compound (124 mg, 0.26mmol, 82% yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.60min, m/z 486.1 [M+H]⁺

5-Amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.25 mmol) gave, after purification the titled compound (0.12 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 504.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 504.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2, 3.3 Hz,1H), 7.38-7.33 (m, 1H), 7.24-7.18 (m, 3H), 6.31 (s, 2H), 4.60 (d, J=6.2Hz, 2H), 4.42-4.34 (m, 1H), 3.98-3.94 (m, 2H), 3.90 (s, 3H), 3.46-3.39(m, 2H), 2.00-1.90 (m, 2H), 1.78-1.76 (m, 2H).

Example 143:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-methoxy-1-methyl-ethyl)pyrazole-4-carboxamide

tert-Butyl N-[(2-methoxy-1-methyl-ethylidene)amino]carbamate

General procedure E, tert-butyl carbazate (3.78 mmol) and methoxyacetone(2.27 mmol) gave, the titled compound (2.27 mmol) as a yellow oil.UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 202.9 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-(2-methoxy-1-methyl-ethyl)pyrazole-4-carbonitrile

Following general procedure O, tert-butylN-[(2-methoxy-1-methyl-ethylidene)amino]carbamate (830 mg, 4.11 mmol),and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol)gave, after purification the titled compound (0.18 mmol). UPLC-MS (Shortacidic): 1.82 min, 337 m/z [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2-methoxy-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.31 mmol), and5-amino-3-(4-bromophenyl)-1-(2-methoxy-1-methyl-ethyl)pyrazole-4-carbonitrile(0.18 mmol) gave, after purification the titled compound (0.13 mmol) asan off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.57 min, 420.1 m/z [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-methoxy-1-methyl-ethyl)pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-(2-methoxy-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.13 mmol) gave, after purification the titled compound (0.03 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.38 min, 438.1 m/z [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.10 min, 438.1 m/z [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.75 (dd, J=7.6, 1.7 Hz, 1H),7.51-7.38 (m, 5H), 7.15 (d, J=8.2 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.31(s, 2H), 4.54 (d, J=6.0 Hz, 2H), 4.48-4.51 (m, 1H), 3.90 (s, 3H),3.69-3.62 (m, 1H), 3.49 (dd, J=9.8, 5.4 Hz, 1H), 3.23 (s, 3H), 1.28 (d,J=6.6 Hz, 3H).

Example 144:5-amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

2,2-Difluorovinyl 4-methylbenzenesulfonate

A solution of 2,2,2-trifluoroethyl tosylate (33.4 mmol) in anhydrous THF(111 mL), at −78° C., and n-butyllithium solution (11 M in hexane, 66.9mmol) was stirred at −78° C. for 20 min, then quenched with a mixture ofwater (20 mL) and THF (20 mL) whilst maintaining internal temperature at−60° C., then warmed to RT and extracted with EtOAc. The combinedorganic extracts were washed with a saturated solution of brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.Purification gave the titled compound (26.9 mmol) as a colourless oil.¹H NMR (400 MHz, DMSO-d₆, δ): 7.86 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.6 Hz,2H), 6.85 (dd, J=15.6, 3.9 Hz, 1H), 2.45 (s, 3H).

(1-Benzyl-4,4-difluoro-pyrrolidin-3-yl) 4-methylbenzenesulfonate

A mixture of 2,2-difluorovinyl 4-methylbenzenesulfonate (26.6 mmol), andN-(methoxymethyl)-N-(trimethyl silylmethyl)benzylamine (106 mmol), undernitrogen, was heated to 130° C. for 5 min. Trifluoroacetic acid (2.66mmol) was added dropwise and stirred for 30 min at 130° C., cooled toRT, concentrated under reduced pressure and triethylamine (2.66 mmol)was added. The residue was then purified to give the titled compound(23.0 mmol) as a light yellow oil. UPLC-MS (ES⁺, Short acidic): 1.98min, m/z 368.0 [M+H]⁺

1-Benzyl-4,4-difluoro-pyrrolidin-3-ol

Magnesium turnings (1.7 g, 64.6 mmol) were added to a solution of(1-benzyl-4,4-difluoro-pyrrolidin-3-yl) 4-methylbenzenesulfonate (12.9mmol) in MeOH (40 mL), under nitrogen, at 0° C. The reaction was stirredat RT for 1 h, water (4 mL) was added slowly followed by hydrochloricacid (5 M, 20 mL). The volatiles were removed under reduced pressure,basified with aqueous KOH to pH 8 and extracted with DCM (×3). Theorganic extracts were combined, dried over a hydrophobic frit, andconcentrated under reduced pressure. The residue was diluted with EtOAcand stirred at RT for 16 h, filtered and concentrated under reducedpressure. The resulting residue was purified to give the titled compound(9.15 mmol) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆, δ): 7.39-7.23 (m,5H), 5.69 (d, J=5.8 Hz, 1H), 4.13-4.01 (m, 1H), 3.66-3.53 (m, 2H),3.15-3.00 (m, 2H), 2.73-2.59 (m, 1H), 2.32-2.26 (m, 1H).

tert-Butyl 3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate

Under an atmosphere of nitrogen, to a solution of1-benzyl-4,4-difluoro-pyrrolidin-3-ol (6.78 mmol) in EtOH (60 mL) wasadded di-tert-butyl dicarbonate (8.14 mmol) followed by palladiumhydroxide (20 wt % on carbon, 1.14 mmol). The reaction was flushed withhydrogen several times, and stirred at RT for 16 h. The reaction wasthen filtered over a pad of Celite® and the filtrate concentrated underreduced pressure. Further purification gave the titled compound (4.95mmol) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆, δ): 6.08 (d, J=5.2 Hz,1H), 4.20 (s, 1H), 3.66-3.55 (m, 3H), 3.22-3.20 (m, 1H), 1.41 (s, 9H).

tert-Butyl3,3-difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate

To a solution of tert-butyl3,3-difluoro-4-hydroxy-pyrrolidine-1-carboxylate (3.04 mmol) inanhydrous DCM (20 mL), at −20° C. and under nitrogen, was added dropwisetrifluoromethanesulfonic anhydride (1 M in DCM, 7.57 mmol). The reactionwas stirred at −20 to −10° C. for 40 min, quenched with aqueous citricacid (0.5 M), basified with saturated aqueous sodium bicarbonatesolution to achieve pH of approximately 4.5 and extracted with DCM. Theorganic extracts were combined, dried over a hydrophobic frit andconcentrated under reduced pressure to give crude the titled compound(2.51 mmol) as brown oil. ¹H NMR (400 MHz, DMSO-d₆, δ): 5.98-5.93 (m,1H), 3.97-3.68 (m, 3H), 3.71-3.67 (m, 1H), 1.43 (s, 9H).

5-Amino-3-(4-bromophenyl)-1H-pyrazole-4-carbonitrile

General procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.76 mmol) andhydrazine hydrate (55-60% in water, 1.9 mmol) without triethylaminegave, after purification the titled compound (0.69 mmol) as a whitesolid. UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 265.9 [M+2]⁺

tert-Butyl4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate

A solution of tert-butyl3,3-difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate(578 mg, 1.59 mmol),5-amino-3-(4-bromophenyl)-1H-pyrazole-4-carbonitrile (300 mg, 1.14 mmol)and cesium carbonate (743 mg, 2.28 mmol) in DMF (12 mL) was heated to90° C. for 2.5 h. The reaction was cooled to RT, diluted with water andextracted with EtOAc. The combined organic extracts were dried oversodium sulfate, filtered and concentrated under reduced pressure.Purification gave the titled compound (105 mg, 0.22 mmol) as orangesolid.

UPLC-MS (ES⁺, Short acidic): 2.06 min, m/z 468.0 [M]⁺

tert-Butyl4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate

General procedure K, tert-butyl4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate(0.22 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.37 mmol) gave,after purification the titled compound (0.15 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.82 min, m/z 553.2 [M+H]⁺

5-Amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[4-[[2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure M, tert-butyl4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate(80 mg, 0.14 mmol) gave, after purification the titled compound (20 mg,0.04 mmol, 29% yield) as light yellow solid. UPLC-MS (ES⁺, Shortacidic): 1.14 min, m/z 471.1 [M+H]⁺.

UPLC-MS (ES⁺, Long acidic): 2.42 min, m/z 471.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.74 (dd, J=7.6, 1.7 Hz, 1H),7.50-7.40 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.05-7.01 (m, 1H), 6.54 (brs, 2H), 5.04-4.96 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.90 (s, 3H),3.54-3.45 (m, 2H), 3.26-3.07 (m, 2H).

Example 145:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[1-(3-pyridyl)ethyl]pyrazole-4-carboxamide

1-(3-Pyridyl)ethanol

Under an atmosphere of nitrogen, bromo(methyl)magnesium (2.7 M indiethyl ether, 0.31 mmol) and a solution of 3-pyridinecarboxaldehyde(1.60 mmol) in THF (3.2 mL) at −78° C. was stirred at RT for 1 h,quenched with MeOH and concentrated under reduced pressure. Purificationgave the titled compound (1.47 mmol) as a clear oil. ¹H NMR (400 MHz,CDCl₃, δ): 8.65-8.58 (m, 1H), 8.56-8.50 (m, 1H), 7.80-7.75 (m, 1H),7.35-7.29 (m, 1H), 4.99 (q, J=6.5 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H)

3-Acetylpyridine

Pyridine (0.04 mL, 0.49 mmol) was added to a solution of pyridiniumchlorochromate (2.20 mmol) and 1-(3-pyridyl)ethanol (1.47 mmol) in DCM(3 mL) at 0° C. The reaction was left to stir at RT for 2 h, with DCMand the black residue obtained was washed with more DCM (×3). Thecombined organics were then passed through a pad of Celite® and thesolvent removed under reduced pressure to afford crude 3-acetylpyridine(0.66 mmol) as a dark oil which was used directly in the next step. ¹HNMR (400 MHz, CDCl₃, δ): 9.27-9.15 (m, 1H), 8.88-8.76 (m, 1H), 8.29 (d,J=7.8 Hz, 1H), 7.53-7.44 (m, 1H), 2.68 (s, 3H)

tert-Butyl N-[1-(3-pyridyl)ethylideneamino]carbamate

Following general procedure E, 3-acetylpyridine (0.66 mmol) gave, afterpurification the titled compound (97 mg, 0.41 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.05 min, m/z 236.0 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-[1-(3-pyridyl)ethyl]pyrazole-4-carbonitrile

A modified general procedure O at RT, tert-butylN-[1-(3-pyridyl)ethylideneamino]carbamate (97 mg, 0.41 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.34 mmol) gave,after purification the titled compound (0.33 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 369.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[1-(3-pyridyl)ethyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-[1-(3-pyridyl)ethyl]pyrazole-4-carbonitrile(0.22 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.54 mmol) gave,after purification the titled compound (0.16 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 453.2 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[1-(3-pyridyl)ethyl]pyrazole-4-carboxamide

General procedure M,N-[[4-[5-amino-4-cyano-1-[1-(3-pyridyl)ethyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.16 mmol) gave, after purification the titled compound (47 mg, 0.10mmol, 62% yield) as a light yellow solid. UPLC-MS (ES⁺, Short acidic):1.20 min, m/z 471.1 [M+H]⁺. UPLC-MS (ES⁺, Long acidic): 2.62 min, m/z471.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 8.53(d, J=1.6 Hz, 1H), 8.47 (dd, J=4.7, 1.4 Hz, 1H), 7.75 (dd, J=7.6, 1.6Hz, 1H), 7.72-7.66 (m, 1H), 7.51-7.34 (m, 6H), 7.15 (d, J=8.3 Hz, 1H),7.07-7.00 (m, 1H), 6.47 (br s, 2H), 5.66 (q, J=6.9 Hz, 1H), 4.54 (d,J=6.0 Hz, 2H), 3.90 (s, 3H), 1.76 (d, J=6.9 Hz, 3H)

Example 146:5-amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-Amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

General procedures K and M,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(0.38 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.77mmol) gave, after purification the titled compound (43 mg, 0.09 mmol,24% yield). UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 504.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 504.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.86 (t, J=6.0 Hz, 1H), 7.49 (dd, J=9.1, 3.3 Hz, 1H),7.38-7.31 (m, 1H), 7.28-7.22 (m, 2H), 7.20 (dd, J=9.1, 4.3 Hz, 1H), 6.28(s, 2H), 4.56 (d, J=6.0 Hz, 2H), 4.42-4.33 (m, 1H), 3.96 (dd, J=11.9,4.1 Hz, 2H), 3.90 (s, 3H), 3.42 (t, J=12.0 Hz, 2H), 2.01-1.96 (m, 2H),1.77 (d, J=12.0 Hz, 2H).

Example 147:5-amino-1-(5,5-dimethyltetrahydrofuran-3-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

2-Methylpent-4-en-2-ol

Anhydrous acetone (136.19 mmol) was added dropwise to an allylmagnesiumbromide solution (1 M in diethyl ether, 272.4 mmol) at 0° C. Afterstirring at 0° C. for 15 min, the reaction mixture was stirred at RT for2 h. A saturated solution of NH₄Cl was added to partition the layers.The aqueous layer was extracted with diethyl ether, washed with waterand a saturated solution of brine, dried over sodium sulfate and allvolatiles were carefully removed under reduced pressure to afford2-methylpent-4-en-2-ol (49.64 mmol) as a colourless oil. ¹H NMR (400MHz, CDCl₃, □): 5.98-5.83 (m, 1H), 5.23-5.09 (m, 2H), 2.26 (d, J=7.6 Hz,2H), 1.29-1.26 (m, 1H), 1.25 (s, 6H)

4-Methylpentane-1,2,4-triol

2-Methylpent-4-en-2-ol (20.0 mmol) was dissolved in tert-butanol (88 mL)and water (88 mL) and ND-mix-beta (16 g) was added. The reaction mixturewas stirred at RT for 72 h. EtOAc (25 mL) and sodium sulfite (12 g) wereadded, the reaction was stirred for 1 h until clear separation of thetwo phases. The aqueous phase was extracted with EtOAc, dried oversodium sulfate and all volatiles removed under reduced pressure toafford crude 4-methylpentane-1,2,4-triol (8.34 mmol) as a colourlessoil. ¹H NMR (400 MHz, CDCl₃, □): 4.19-4.07 (m, 1H), 3.75-3.60 (m, 2H),3.55-3.44 (m, 1H), 2.41 (br s, 1H), 2.16-2.00 (m, 1H), 1.78 (dd, J=14.5,10.8 Hz, 1H), 1.50 (dd, J=14.5, 2.3 Hz, 1H), 1.37 (s, 3H), 1.33 (s, 3H).

5,5-Dimethyltetrahydrofuran-3-ol

4-Methylpentane-1,2,4-triol (8.35 mmol) was dissolved in DCM (40 mL),the reaction mixture was purged with nitrogen, then p-toluenesulfonylchloride (12.52 mmol) and triethylamine (25.04 mmol) were added. Thereaction mixture was heated to reflux and stirred for 48 h. A saturatedsolution of NH₄Cl was added to partition the layers, the organic layerwas extracted with DCM, washed with a saturated solution of brine, driedover sodium sulfate and all volatiles were removed under reducedpressure. Purification by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane to afford5,5-dimethyltetrahydrofuran-3-ol (3.56 mmol) as a colourless oil. ¹H NMR(400 MHz, CDCl₃, □): 4.57-4.46 (m, 1H), 3.97 (dd, J=9.9, 4.5 Hz, 1H),3.82 (ddd, J=9.9, 2.5, 1.2 Hz, 1H), 2.04 (dd, J=13.5, 6.5 Hz, 1H), 1.82(ddd, J=13.5, 2.5, 1.2 Hz, 1H), 1.78-1.69 (m, 1H), 1.41 (s, 3H), 1.25(s, 3H)

5,5-Dimethyltetrahydrofuran-3-one

To a solution of 5,5-dimethyltetrahydrofuran-3-ol (1.93 mmol) in DCM (10mL) was added dess martin periodinane (2.12 mmol) at RT under nitrogenatmosphere and then allowed to stir for 72 h. The mixture was quenchedwith a saturated solution of sodium thiosulfate and then a saturatedsolution of NaHCO₃. Phases were separated and organic phase was driedover sodium sulfate and filtered. The solvent was concentrated underreduced pressure to afford crude the titled compound (1.93 mmol) whichwas used immediately in the next step. ¹H NMR (400 MHz, CDCl₃, □): 4.06(s, 2H), 2.38 (s, 2H), 1.42 (s, 6H).

tert-Butyl N-[(5,5-dimethyltetrahydrofuran-3-ylidene)amino]carbamate

General procedure E, tert-butyl carbazate (1.97 mmol) and5,5-dimethyltetrahydrofuran-3-one (1.93 mmol) gave crude the titledcompound (mixture of isomers, 1.93 mmol) as a yellow oil. ¹H NMR (400MHz, CDCl₃, □, isomer 1 and isomer 2): isomer 1: 5.94 (s, 1H), 4.49-4.45(m, 2H), 2.36-2.30 (m, 2H), 1.48 (s, 9H), 1.36 (s, 6H) and isomer 2:5.94 (s, 1H), 4.38-4.32 (m, 2H), 2.64-2.58 (m, 2H), 1.48 (s, 9H), 1.33(s, 6H)

5-Amino-3-(4-bromophenyl)-1-(5,5-dimethyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile

To a solution of tert-ButylN-[(5,5-dimethyltetrahydrofuran-3-ylidene)amino]carbamate (1.93 mmol) inTHF (10 mL) was added a borane dimethyl sulfide complex solution (2 M inTHF, 3.43 mmol). The reaction was stirred at RT for 1 h and wasconcentrated under reduced pressure. The residue was taken up with MeOH(10 mL) and hydrochloric acid (12 M, 20.15 mmol) then heated to refluxfor 14 h, cooled and concentrated under reduced pressure. The residuewas taken up with EtOH (10 mL), followed by addition of2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.38 mmol) andtriethylamine (1.9 mmol), and heated to reflux for 16 h. The solvent wasevaporated under reduced pressure and the residue was purified by flaskcolumn chromatography on silica gel eluting with 0-100% EtOAc in heptaneto give the titled compound (0.12 mmol) as a yellow oil. UPLC-MS (ES⁻,Short acidic): 1.86 min, m/z 360.9 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(5,5-dimethyltetrahydrofuran-3-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

General procedure K, 5-amino-3-(4-bromophenyl)-1-(5,5-dimethyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile (0.14 mmol), and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.19 mmol) gave,after purification by flash column chromatography on silica gel elutingwith 20-100% EtOAc in heptane, the titled compound (0.1 mmol) as a paleyellow solid. UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 446.0 [M+H]⁺

5-Amino-1-(5,5-dimethyltetrahydrofuran-3-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

General procedure L,N-[[4-[5-amino-4-cyano-1-(5,5-dimethyltetrahydrofuran-3-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(0.10 mmol) gave, after purification the titled compound (0.03 mmol) asa beige solid. UPL-CMS (ES⁺, Short acidic): 1.44 min, m/z 464.1 [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.32 min, m/z 464.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 8.66 (t, J=6.0 Hz, 1H), 7.68 (dd, J=7.6, 1.7 Hz, 1H),7.42-7.33 (m, 5H), 7.07 (d, J=8.3 Hz, 1H), 6.96 (t, J=7.1 Hz, 1H), 6.34(s, 2H), 4.99-4.92 (m, 1H), 4.45 (d, J=6.1 Hz, 2H), 3.98 (t, J=8.1 Hz,1H), 3.82 (s, 3H), 3.80-3.78 (m, 1H), 2.10 (dd, J=3.5, 2.6 Hz, 2H), 1.24(s, 3H), 1.16 (s, 3H).

Example 148:5-amino-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(1.57 mmol) gave, after purification by flash chromatography on silicagel eluting with 15-75% EtOAc in heptane, the titled compound (0.77mmol) as a solid. UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 339.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide

General procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile(130 mg, 0.38 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (208 mg, 0.77 mmol)gave crude the titled compound (136 mg, 0.29 mmol, 76% yield) as asolid, which was used without further purification. UPLC-MS (ES⁺, Shortacidic): 1.56 min, m/z 468.1 [M+H]⁺

5-Amino-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

Following general procedure L,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide(136 mg, 0.29 mmol) gave, after purification, the titled compound (0.04mmol) as a solid. UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 486.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.12 min, m/z 486.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 7.72 (dd, J=7.6, 1.8 Hz,1H), 7.51-7-47 (m, 1H), 7.28-7.22 (m, 2H), 7.18-7.15 (m, 1H), 7.04 (td,J=7.6, 0.9 Hz, 1H), 6.28 (s, 2H), 4.56 (d, J=6.0 Hz, 2H), 4.42-4.34 (m,1H), 3.96 (dd, J=11.5, 4.1 Hz, 2H), 3.91 (s, 3H), 3.45-3.39 (m, 2H),2.01-1.91 (m, 2H), 1.80-1.75 (m, 2H).

Example 149:5-amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

General procedure H,2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(0.79 mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (240 mg,1.57 mmol) gave after purification the titled compound (0.34 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 339.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.16 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.32mmol) gave the titled compound (0.16 mmol) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.68 min, m/z 486.1 [M+H]⁺

5-Amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(0.16 mmol) gave after purification the titled compound (0.05 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.50 min, m/z 504.1[M+H]⁺. UPLC-MS (ES⁺, Long acidic): 3.43 min, m/z 504.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, δ): 8.86 (t, J=6.0 Hz, 1H), 7.48 (dd, J=9.1, 3.3 Hz,1H), 7.39-7.31 (m, 1H), 7.28-7.16 (m, 3H), 6.31 (s, 2H), 4.55 (d, J=6.0Hz, 2H), 4.33-4.21 (m, 1H), 3.92-3.73 (m, 5H), 3.52 (t, J=10.5 Hz, 1H),3.35-3.26 (m, 1H), 2.03-1.94 (m, 2H), 1.79-1.58 (m, 2H).

Example 150:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-sec-butyl-pyrazole-4-carboxamide

tert-Butyl N-[1-methylpropylideneamino]carbamate

Following general procedure E, tert-butyl carbazate (7.57 mmol), and2-butanone (9.08 mmol) gave the titled compound (7.57 mmol) as a yellowoil. UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 186.9 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-sec-butyl-pyrazole-4-carbonitrile

General procedure O, tert-butyl N-[1-methylpropylideneamino]carbamate(7.39 mmol), and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(0.76 mmol) gave, after purification, the titled compound (0.38 mmol) asan off-white solid. UPLC (ES⁺, Short acidic): 1.95 min, 321.0 m/z [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-sec-butyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

General procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.69 mmol), and5-amino-3-(4-bromophenyl)-1-sec-butyl-pyrazole-4-carbonitrile (0.40mmol) gave, after purification, the titled compound (0.26 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): 1.66 min, 404.1 m/z [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-sec-butyl-pyrazole-4-carboxamide

General procedure M,N-[[4-(5-amino-4-cyano-1-sec-butyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide(0.06 mmol) gave, after purification the titled compound (0.04 mmol) asa white solid. UPLC-MS (ES⁺, Short acidic): 1.49 min, 422.2 m/z [M+H]⁺.UPLC-MS (ES⁺, Long acidic): 3.34 min, 422.2 m/z [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.6, 1.7 Hz, 1H),7.51-7.45 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.31(s, 2H), 4.54 (d, J=6.0 Hz, 2H), 4.28-4.16 (m, 1H), 3.90 (s, 3H),1.88-1.72 (m, 1H), 1.72-1.56 (m, 1H), 1.31 (d, J=6.5 Hz, 3H), 0.76 (t,J=13 Hz, 3H).

Example 151:5-amino-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.16 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (0.32 mmol) gave,after purification, titled compound (0.15 mmol, 93% yield) as a yellowsolid. UPLC-MS: (ES⁺, Short acidic): 1.63 min, m/z 468.1 [M+H]⁺

5-Amino-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide(65 mg, 0.14 mmol) gave, after purification, titled compound (10 mg,0.02 mmol, 15% yield) as an off-white solid. UPLC-MS: (ES⁺, Shortacidic): 1.49 min, m/z 486.1 [M+H]⁺ UPLC-MS: (ES⁺, Long acidic): 3.32min, m/z 468.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.77 (t, J=5.9 Hz, 1H), 7.71 (dd, J=7.7,1.7 Hz, 1H), 7.51-7.47 (m, 1H), 7.26-7.22 (m, 2H), 7.16 (d, J=8.3 Hz,1H), 7.06-7.02 (m, 1H), 6.32 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 4.31-4.24(m, 1H), 3.91-3.81 (m, 5H), 3.55-3.50 (m, 1H), 3.37-3.26 (m, 1H),2.02-1.96 (m, 2H), 1.76-1.64 (m, 2H).

Example 152:5-amino-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(250 mg, 0.98 mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (163mg, 1.18 mmol) gave, after purification, titled compound (70 mg, 0.22mmol). UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 325.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(70 mg, 0.22 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (117 mg, 0.43 mmol)gave, after purification, titled compound (0.14 mmol, 63% yield) as awhite solid. UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 454.1 [M+H]⁺

5-Amino-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide(60 mg, 0.13 mmol) gave, after purification, titled compound (18 mg,0.04 mmol, 29% yield) as a solid. UPLC-MS (ES⁺, Short acidic): 1.46 min,m/z 472.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.16 min, m/z 472.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 7.72 (dd, J=7.6,1.7 Hz, 1H), 7.51-7.47 (m, 1H), 7.29-7.22 (m, 2H), 7.16 (d, J=8.3 Hz,1H), 7.06-7.02 (m, 1H), 6.30 (s, 2H), 4.98-4.91 (m, 1H), 4.55 (d, J=6.0Hz, 2H), 4.01-3.92 (m, 2H), 3.91 (s, 3H), 3.83-3.76 (m, 2H), 2.30-2.20(m, 2H).

Example 153:5-amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(60 mg, 0.18 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (134 mg,0.46 mmol) gave, after purification, titled compound (40 mg, 0.08 mmol,46% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z472.1 [M+H]⁺

5-Amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(39 mg, 0.08 mmol) gave, after purification, titled compound (18 mg,0.04 mmol, 43% yield). UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 490.1[M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.29 min, m/z 490.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.86 (t, J=6.3 Hz, 1H), 7.49 (dd, J=9.1,3.3 Hz, 1H), 7.38-7.31 (m, 1H), 7.29-7.17 (m, 3H), 6.30 (s, 2H),4.98-4.91 (m, 1H), 4.55 (d, J=5.9 Hz, 2H), 4.01-3.92 (m, 2H), 3.90 (s,3H), 3.84-3.76 (m, 2H), 2.30-2.21 (m, 2H).

Example 154:5-amino-1-cyclopentyl-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,3-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile(250 mg, 0.98 mmol) and cyclopentylhydrazine hydrochloride (174 mg, 1.28mmol) gave, after purification, titled compound (173 mg, 0.54 mmol, 55%yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.97 min, m/z 322.9 [M]⁺

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(79 mg, 0.25 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (120 mg,0.42 mmol) gave, after purification, titled compound (91 mg, 0.19 mmol,79% yield) as an white solid.

UPLC-MS (ES⁺, Short acidic): 1.81 min, m/z 470.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(90 mg, 0.19 mmol) gave, after purification, titled compound (65 mg,0.13 mmol, 70% yield) as white solid. UPLC-MS (ES⁺, Short acidic): 1.66min, m/z 488.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.86 min, m/z 488.2[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.38-7.33 (m, 1H), 7.25-7.18 (m, 3H), 6.26 (br s, 2H),4.67-4.59 (m, 1H), 4.60 (d, J=5.9 Hz, 2H), 3.90 (s, 3H), 2.01-1.94 (m,2H), 1.92-1.83 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.56 (m, 2H).

Example 155:5-amino-1-cyclopentyl-3-[2,3-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(86 mg, 0.27 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (123 mg, 0.45 mmol)gave, after purification, titled compound (111 mg, 0.25 mmol, 92% yield)as an white solid.

UPLC-MS (ES⁻, Short acidic): 1.77 min, m/z 450.1 [M−H]⁻

5-Amino-1-cyclopentyl-3-[2,3-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-2-methoxy-benzamide(110 mg, 0.24 mmol) gave, after purification, titled compound (74 mg,0.16 mmol, 65% yield) as white solid. UPLC-MS (ES⁺, Short acidic): 1.65min, m/z 470.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.75 min, m/z 470.2[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.6,1.7 Hz, 1H), 7.52-7.49 (m, 1H), 7.26-7.20 (m, 2H), 7.17 (d, J=8.2 Hz,1H), 7.06-7.03 (m, 1H), 6.26 (br s, 2H), 4.67-4.60 (m, 1H), 4.60 (d,J=6.0 Hz, 2H), 3.91 (s, 3H), 2.03-1.93 (m, 2H), 1.92-1.83 (m, 2H),1.82-1.73 (m, 2H), 1.63-1.54 (m, 2H).

Example 156:5-amino-1-cyclopentyl-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,5-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(250 mg, 0.98 mmol) and cyclopentylhydrazine hydrochloride (161 mg, 1.18mmol) gave, after purification, titled compound (250 mg, 0.77 mmol, 79%yield) UPLC-MS (ES⁺, Short acidic) 1.98 min, m/z 323.0 [M]⁺

N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-cyclopentyl-pyrazole-4-carbonitrile(125 mg, 0.39 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (158 mg, 0.58 mmol)gave, after purification, titled compound (75 mg, 0.17 mmol, 43% yield)as a white solid. UPLC-MS (ES⁺, Short acidic) 1.78 min, m/z 452.1 [M+H]⁺

5-Amino-1-cyclopentyl-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2,5-difluoro-phenyl]methyl]-2-methoxy-benzamide(135 mg, 0.30 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 50-100% EtOAc in heptane andthen by SCX-SPE cartridge,5-amino-1-cyclopentyl-3-[2,5-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(63 mg, 0.13 mmol, 45% yield) as a light brown solid. UPLC-MS (ES⁺,Short acidic): 1.65 min, m/z 470.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.78 min, m/z 470.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 7.72 (dd, J=7.7,1.7 Hz, 1H), 7.51-7.47 (m, 1H), 121-HI (m, 2H), 7.17 (d, J=8.3 Hz, 1H),7.06-7.02 (m, 1H), 6.22 (s, 2H), 4.67-4.57 (m, 1H), 4.55 (d, J=6.0 Hz,2H), 3.91 (s, 3H), 2.03-1.83 (m, 4H), 1.79-1.77 (m, 2H), 1.60-1.57 (m,2H).

Example 157:5-amino-3-[2,3-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Tetrahydropyran-3-ylhydrazine hydrochloride

To a solution of 3-hydroxytetrahydropyrane (1.8 mL, 19.58 mmol) intoluene (30 mL), under nitrogen, was added triphenylphosphine (7.7 g,29.37 mmol) and di-tert-butylazodicarboxylate (5.4 g, 23.50 mmol). Thereaction mixture was stirred at RT for 60 h. The reaction mixture wasconcentrated then suspended in MeOH (55 mL), followed by addition of ahydrogen chloride solution (4 M in dioxane, 39.17 mL, 156.7 mmol). Thereaction mixture was stirred at RT for 16 h, filtered, and the filtratewas concentrated under reduced pressure. EtOAc was then added to theresulting residue followed by filtration. The solid collected was washedwith EtOAc to afford titled compound (2.99 g, 19.58 mmol, assumedquantitative yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆, δ): 3.91-3.82 (m, 1H), 3.76-3.58 (m, 1H),3.45-3.29 (m, 2H), 3.04-2.94 (m, 1H), 2.00-1.90 (m, 1H), 1.77-1.65 (m,1H), 1.62-1.37 (m, 2H).

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(50 mg, 0.15 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (81 mg, 0.30 mmol)afforded crude titled compound (0.15 mmol) as a yellow solid. UPLC-MS(ES⁺, Short acidic): 1.63 min, m/z 468.1 [M+H]⁺

5-Amino-3-[2,3-difluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-2-methoxy-benzamide(98 mg, 0.21 mmol) afforded, after purification by flash columnchromatography on silica gel eluting with 0-5% MeOH in DCM, titledcompound (13 mg, 0.02 mmol, 12% yield) as a pale yellow solid. UPLC-MS(ES⁺, Short acidic): 1.50 min, m/z 486.1 [M+H]⁺ UPLC-MS (ES⁺, Longacidic): 3.41 min, m/z 486.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (t, J=6.0 Hz, 1H), 7.75 (dd, J=7.6,1.7 Hz, 1H), 7.52-7.47 (m, 1H), 7.26-7.16 (m, 3H), 7.07-7.03 (m, 1H),6.35 (s, 2H), 4.60 (d, J=5.9 Hz, 2H), 4.32-4.25 (m, 1H), 3.91-3.83 (m,5H), 3.52 (t, J=10.5 Hz, 1H), 3.32-3.28 (m, 1H), 2.04-1.93 (m, 2H),1.77-1.65 (m, 2H).

Example 158:5-amino-3-[3,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-3,5-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-chloro-3,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(166 mg, 0.65 mmol), and tetrahydropyran-3-ylhydrazine hydrochloride(150 mg, 0.98 mmol) afforded, after purification, titled compound (32mg, 0.09 mmol, 14% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.94 min, m/z 339.0 [M]⁺

N-[[(4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-3,5-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.09 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.23mmol) afforded, after purification, titled compound (0.10 mmol) as ayellow solid. UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 486.1 [M+H]⁺

5-Amino-3-[3,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,6-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(47 mg, 0.10 mmol) afforded, after purification, titled compound (22 mg,0.04 mmol, 39% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): E58min, m/z 504.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.63 min, m/z 504.1[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.66 (t, J=6.0 Hz, 1H), 7.47 (dd, J=9.2,3.3 Hz, 1H), 7.36-7.31 (m, 1H), 7.22-7.16 (m, 3H), 6.30 (s, 2H), 4.60(d, J=5.5 Hz, 2H), 4.31-4.24 (m, 1H), 3.87-3.85 (m, 5H), 3.54 (t, J=10.5Hz, 1H), 3.39-3.25 (m, 1H), 2.04-1.98 (m, 2H), 1.78-1.63 (m, 2H).

Example 159:5-amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile(150 mg, 0.59 mmol) and tetrahydropyran-3-ylhydrazine hydrochloride (225mg, 1.47 mmol) afforded, after purification, titled compound (60 mg,0.18 mmol, 30% yield) as a brown solid. UPLC-MS (ES⁺, Short acidic):1.79 min, m/z 339.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydropyran-3-yl-pyrazole-4-carbonitrile(0.18 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.53mmol) afforded, after purification, titled compound (0.22 mmol, assumedquantitative yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.69min, m/z 486.1 [M+H]⁺

5-Amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydropyran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydropyran-3-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(108 mg, 0.22 mmol) afforded, after purification, titled compound (25mg, 0.04 mmol, 20% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 504.1 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 3.54 min, m/z 504.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.39-7.33 (m, 1H), 7.26-7.18 (m, 3H), 6.35 (s, 2H), 4.60(d, J=5.9 Hz, 2H), 4.33-4.26 (m, 1H), 3.90-3.84 (m, 5H), 3.52 (t, J=10.5Hz, 1H), 3.32-3.28 (m, 1H), 2.00-1.96 (m, 2H), 1.77-1.61 (m, 2H).

Example 160:5-amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1H-pyrazole-4-carbonitrile

To a solution of2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (2.23 g,7.94 mmol) in EtOH (90 mL) was added hydrazine hydrate (55-60% in water,2.71 mL, 27.8 mmol). The reaction mixture was heated at 90° C. for 1 h.The reaction was cooled to RT and, the solvent was removed under reducedpressure to afford crude titled compound (1.88 g, 6.70 mmol, 84% yield)as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 282.9 [M+2]⁺

tert-Butyld-[5-amino-3-(4-bromo-3-fluoro-phenyl)-4-cyano-pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate

tert-Butyl3,3-difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate(626 mg, 1.73 mmol),5-amino-3-(4-bromo-3-fluoro-phenyl)-1H-pyrazole-4-carbonitrile (370 mg,1.32 mmol) and cesium carbonate (858 mg, 2.63 mmol) were suspended inDMF (8 mL) and heated at 90° C. for 2.5 h. The reaction was cooled to RTand diluted with water. Work up and purification gave titled compound(0.22 mmol, 16% yield) as a beige solid. UPLC-MS (ES⁺, Short acidic):2.11 min, m/z 488.0 [M+2]⁺

tert-Butyl4-[5-amino-4-cyano-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate

Following general procedure K, tert-butyl4-[5-amino-3-(4-bromo-3-fluoro-phenyl)-4-cyano-pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate(120 mg, 0.25 mmol), and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (114 mg, 0.42 mmol)gave, after purification, titled compound (102 mg, 0.17 mmol) as lightyellow solid. UPLC-MS (ES⁺, Short acidic): 1.91 min, m/z 571.2 [M+H]⁺

5-Amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M, tert-butyl4-[5-amino-4-cyano-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate(96 mg, 0.17 mmol) gave, after purification, titled compound (57 mg,0.12 mmol, 69% yield) as white solid. UPLC-MS (ES⁺, Short acidic): 1.24min, m/z 489.1 [M+E1]⁺ UPLC-MS (ES⁺, Long acidic): 2.56 min, m/z 489.1[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.7,1.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.36-7.30 (m, 2H), 7.17 (d, J=8.3 Hz,1H), 7.07-7.03 (m, 1H), 6.48 (br s, 2H), 5.04-4.97 (m, 1H), 4.58 (d,J=6.0 Hz, 2H), 3.91 (s, 3H), 3.54-3.44 (m, 2H), 3.24-3.08 (m, 2H).

Example 161:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(1-tetrahydropyran-4-ylethyl)pyrazole-4-carboxamide

1-Tetrahydropyran-4-ylethanone hydrazone

To a solution of 1-tetrahydro-2H-pyran-4-ylethanone (166 mg, 1.30 mmol)in MeOH (7.5 mL) hydrazine hydrate (55-60% in water, 0.90 mL, 17.61mmol) was added. The reaction mixture was heated to reflux for 16 h,cooled and concentrated under reduced pressure to give crude1-tetrahydropyran-4-ylethanone hydrazone (171 mg, 1.20 mmol, 93% yield)as a colourless oil. ¹H NMR (400 MHz, CDCl₃, □): 4.92 (s, 2H), 4.03-3.98(m, 2H), 3.45-3.40 (m, 2H), 2.38-2.30 (m, 1H), 1.73 (s, 3H), 1.65-1.63(m, 4H).

5-Amino-3-(4-bromophenyl)-1-(T-tetrahydropyran-4-ylethyl)pyrazole-4-carbonitrile

A borane tetrahydrofuran complex solution (1 M in THF, 3.00 mL, 3.00mmol) was added to a solution of 1-tetrahydropyran-4-ylethanonehydrazone (171 mg, 1.20 mmol) in THF (7 mL) at 0° C. The reactionmixture was stirred at RT for 16 h and concentrated under reducedpressure. The residue was taken up with EtOH (10 mL) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (200 mg, 0.76mmol) was added. The reaction mixture was heated to reflux for 16 h togive titled compound (60 mg, 0.16 mmol, 21% yield) as a brown oil.

UPLC-MS: (ES⁺, Short acidic): 1.90 min, m/z 377.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(1-tetrahydropyran-4-ylethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(1-tetrahydropyran-4-ylethyl)pyrazole-4-carbonitrile(0.16 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (0.80mmol) gave, after purification, titled compound (0.16 mmol) as an yellowoil. UPLC-MS: (ES⁺, Short acidic): 1.67 min, m/z 478.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(1-tetrahydropyran-4-ylethyl)pyrazole-4-carboxamide

Following general procedure L,N-[[4-[5-amino-4-cyano-1-(1-tetrahydropyran-4-ylethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(76 mg, 0.16 mmol) gave, after purification, titled compound (10 mg,0.02 mmol, 13% yield) as an off-white solid.

UPLC-MS: (ES⁺, Short acidic): 1.51 min, m/z 496.2 [M+H]⁺ UPLC-MS: (ES⁺,Long acidic): 3.28 min, m/z 496.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.82 (t, J=6.0 Hz, 1H), 7.50 (dd, J=9.2,3.1 Hz, 1H), 7.45-7.39 (m, 4H), 7.36-7.31 (m, 1H), 7.18 (dd, J=9.0, 4.3Hz, 1H), 6.34 (s, 2H), 4.54 (d, J=5.9 Hz, 2H), 4.10-4.03 (m, 1H),3.93-3.83 (m, 4H), 3.82-3.74 (m, 1H), 3.29-3.22 (m, 1H), 3.19-3.12 (m,1H), 2.03-1.90 (m, 1H), 1.71-1.65 (m, 1H), 1.37 (d, J=6.5 Hz, 3H),1.28-1.16 (m, 2H), 1.07-1.03 (m, 1H).

Example 162:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carbonitrile

Following a modified general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (2 mmol) and[(3S)-tetrahydrofuran-3-yl]hydrazine hydrochloride (3.65 mmol) gavecrude titled compound (2 mmol). UPLC-MS (ES⁺, Short acidic): 1.75 min,m/z 335.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[(3S)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (1229 mg,4.25 mmol) and5-amino-3-(4-bromophenyl)-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carbonitrile(644 mg, 1.93 mmol) gave crude titled compound (840 mg, 1.93 mmol,assumed quantitative yield). LC-MS (ES⁺, Short acidic): 1.59 min, m/z436.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(3S)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[(3S)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(840 mg, 1.93 mmol) gave, after purification, titled compound (293 mg,0.65 mmol, 34% yield) as a white solid. UPLC-MS (ES⁺, Long acidic): 3.09min, m/z 454.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, □): 8.83 (t, J=6.2 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.47-7.39 (m, 4H), 7.37. 7.31 (m, 1H), 7.22-7.16 (m, 1H),6.39 (br s, 2H), 4.97-4.89 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 4.02-3.91(m, 2H), 3.89 (s, 3H), 3.83-3.77 (m, 2H), 2.31-2.21 (m, 2H).

Example 163a:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide—Isomer1 and Example 163b—Isomer 2

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide(150 mg, 0.31 mmol) was purified by preparative SFC (SFC-B) to give,after evaporation and lyophilization,5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide(isomer 1, 44 mg, 0.09 mmol, 29% yield) and5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide(isomer 2, 48 mg, 0.10 mmol, 32% yield) as white solids. UPLC-MS (ES⁺,Short acidic, Isomer 1): 1.53 min, m/z 480.1 [M+H]⁺ UPLC-MS (ES⁺, Longacidic, Isomer 1): 3.55 min, m/z 480.1 [M+H]⁺ SFC (SFC-A, Isomer 1):1.95 min

¹H NMR (DMSO-d₆, □, Isomer 1): 8.83 (t, J=6.1 Hz, 1H), 7.51 (dd, J=9.3,3.3 Hz, 1H), 7.48-7.39 (m, 4H), 7.33 (ddd, J=9.0, 7.9, 3.3 Hz, 1H), 7.18(dd, J=9.0, 4.3 Hz, 1H), 6.67 (s, 2H), 5.35-5.22 (m, 1H), 4.55 (d, J=6.1Hz, 2H), 3.89 (s, 3H), 1.61 (d, J=6.7 Hz, 3H) UPLC-MS (ES⁺, Shortacidic, Isomer 2): 1.53 min, m/z 480.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic,Isomer 2): 3.55 min, m/z 480.1 [M+H]⁺ SFC (SFC-A, Isomer 2): 2.26 min

¹H NMR (DMSO-d₆, □, Isomer 2): 8.84 (t, J=6.1 Hz, 1H), 7.52 (dd, J=9.3,3.3 Hz, 1H), 7.49-7.40 (m, 4H), 7.38-7.31 (m, 1H), 7.19 (dd, J=9.0, 4.3Hz, 1H), 6.68 (s, 2H), 5.34-5.24 (m, 1H), 4.56 (d, J=6.1 Hz, 2H), 3.90(s, 3H), 1.62 (d, J=6.7 Hz, 3H)

Example 164:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (300 mg, 1.14mmol), and [(3R)-tetrahydrofuran-3-yl]hydrazine hydrochloride (190 mg,1.37 mmol) gave, after purification, titled compound (210 mg, 0.63 mmol,55% yield).

UPLC (ES⁺, Short acidic): 1.77 min, m/z 335.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[(3R)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (334 mg,1.15 mmol), and5-amino-3-(4-bromophenyl)-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carbonitrile(150 mg, 0.45 mmol) gave, after purification, titled compound (48 mg,0.11 mmol, 25% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 436.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(3R)-tetrahydrofuran-3-yl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[(3R)-tetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(48 mg, 0.11 mmol) gave, after purification, titled compound (25 mg,0.05 mmol, 50% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.45 min, 454.1 m/z [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.08 min, 454.1m/z [M+H]⁺ ¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.1 Hz, 1H), 7.51(dd, J=9.2, 3.3 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H),7.39-7.30 (m, 1H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 6.40 (s, 2H), 4.98-4.89(m, 1H), 4.55 (d, J=6.1 Hz, 2H), 4.03-3.92 (m, 2H), 3.90 (s, 3H),3.85-3.76 (m, 2H), 2.30-2.22 (m, 2H).

Example 165:5-amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2,3-difluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromo-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile (140mg, 0.47 mmol), and (2,2,2-trifluoro-1-methyl-ethyl)hydrazinehydrochloride (100 mg, 0.61 mmol) gave after purification, titledcompound (129 mg, 0.33 mmol, 70% yield) as white solid.

UPLC-MS (ES⁺, Short acidic): 1.86 min, m/z 397.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromo-2,3-difluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(124 mg, 0.31 mmol), and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (154 mg,0.53 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(120 mg, 0.24 mmol, 77% yield) as a light yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.75 min, m/z 498.1 [M+H]⁺

5-Amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(110 mg, 0.22 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in DCM,5-amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide(73 mg, 0.14 mmol, 64% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 516.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.80 min, m/z 516.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.88 (t, J=5.9 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.38-7.33 (m, 1H), 7.28-7.18 (m, 3H), 6.61 (s, 2H),5.36-5.27 (m, 1H), 4.61 (d, J=5.9 Hz, 2H), 3.90 (s, 3H), 1.61 (d, J=6.7Hz, 3H)

Example 166:5-amino-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(11 mg, 0.02 mmol) and cesium carbonate (15 mg, 0.05 mmol) weresuspended in DMF (2 mL). The mixture was cooled to −10° C., purged withnitrogen, and a 0.2 M solution of iodomethane in DMF (0.1 mL, 0.02 mmol)was then added. The reaction was allowed to warm to RT and stirred for16 h. Work up and purification gave titled compound (4 mg, 0.01 mmol,35% yield) as light yellow solid. UPLC-MS (ES⁺, Short acidic): 1.25 min,m/z 503.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 2.73 min, m/z 503.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.76 (dd, J=7.7,1.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.34-7.27 (m, 2H), 7.17 (d, J=8.4 Hz,1H), 7.06-7.02 (m, 1H), 6.51 (s, 2H), 5.25-5.16 (m, 1H), 4.58 (d, J=6.0Hz, 2H), 3.91 (s, 3H), 3.29-3.17 (m, 3H), 2.91-2.70 (m, 1H), 2.36 (s,3H).

Example 167:5-amino-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(40 mg, 0.09 mmol) and cesium carbonate (55 mg, 0.17 mmol) weresuspended in DMF (3 mL). The mixture was cooled to −15° C. purged withnitrogen, and a solution of iodomethane (0.9 M in THF, 0.2 mL, 0.18mmol) was then added dropwise. The reaction was allowed to warm to RTand stirred for 16 h. Work up and purification gave titled compound (5mg, 0.01 mmol, 12% yield) was obtained as white solid. UPLC-MS (ES⁺,Short acidic): 1.19 min, m/z 485.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic):2.62 min, m/z 485.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.0 Hz, 1H), 7.74 (dd, J=7.6,1.7 Hz, 1H), 7.49-7.40 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 7.05-7.01 (m,1H), 6.56 (s, 2H), 5.22-5.13 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.89 (s,3H), 3.28-3.15 (m, 3H), 2.86-2.73 (m, 1H), 2.34 (s, 3H).

Example 168:5-amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

5-Amino-3-(4-chloro-2,5-difluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

Following general procedure H, (2,2,2-trifluoro-1-methyl-ethyl)hydrazinehydrochloride (96 mg, 0.58 mmol) and2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]propanedinitrile(114 mg, 0.45 mmol) gave crude 5 titled compound (156 mg, 0.44 mmol,assumed quantative yield).

UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 351.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (257 mg,0.89 mmol) and5-amino-3-(4-chloro-2,5-difluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(156 mg, 0.44 mmol) gave, titled compound (221 mg, 0.44 mmol, 98%yield). UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 498.1 [M+H]⁺

5-Amino-3-[2,5-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2,5-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(221 mg, 0.44 mmol) gave, after purification titled compound (0.10mmol). UPLC-MS (ES⁺, Long acidic): 3.77 min, m/z 516.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.1 Hz, 1H), 7.49 (dd, J=9.2,3.3 Hz, 1H), 7.38-7.31 (m, 1H), 7.29-7.22 (m, 3H), 6.57 (br s, 2H),5.36-5.27 (m, 1H), 4.56 (d, J=5.9 Hz, 2H), 3.90 (s, 3H), 1.60 (d, J=7.0Hz, 3H).

Example 169:5-amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (128 mg,0.44 mmol) and tert-butyl4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate(81 mg, 0.17 mmol) gave, after purification, titled compound (50 mg,0.09 mmol, 51% yield) as a pale yellow solid. UPLC-MS (ES⁻, Shortacidic): 1.86 min, 569.2 m/z [M−H]⁻

5-Amino-1-(4,4-difluoropyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M, tert-butyl4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-3,3-difluoro-pyrrolidine-1-carboxylate(50 mg, 0.09 mmol) gave, after purification, titled compound (13 mg,0.05 mmol) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.20 min, 489.1 m/z [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 2.61 min, 489.2 m/z [M+H]⁺ ¹H NMR (400 MHz, DMSO-d₆, δ):8.84 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2, 3.3 Hz, 1H), 7.47 (d, J=8.3 Hz,2H), 7.42 (d, J=8.3 Hz, 2H), 7.38-7.30 (m, 1H), 7.19 (dd, J=9.1, 4.3 Hz,1H), 6.54 (s, 2H), 5.08-4.94 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 3.90 (s,3H), 3.59-3.43 (m, 2H), 3.26-3.07 (m, 2H).

Example 170:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

N-[1-(Trifluoromethyl)propylideneamino]benzamide

Following general procedure S, 1,1,1-trifluoro-2-butanone (0.45 mL, 3.30mmol) and benzhydrazide (2.20 mmol) afforded crude titled compound (487mg, 2.0 mmol, 91% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.70 min, m/z 245.0 [M+H]⁺

N′-[1-(Trifluoromethyl)propyl]benzohydrazide

Following general procedure T,N-[1-(trifluoromethyl)propylideneamino]benzamide (487 mg, 2.0 mmol)afforded crude titled compound (487 mg, 1.98 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 247.0 [M+H]⁺

1-(Trifluoromethyl)propylhydrazine hydrochloride

Following general procedure U,N′-[1-(trifluoromethyl)propyl]benzohydrazide (487 mg, 1.98 mmol)afforded crude titled compound (1.98 mmol, assumed quantitative yield)as a white solid.

¹H NMR (400 MHz, DMSO-d₆, δ): 3.64-3.59 (m, 1H), 1.76-1.53 (m, 2H), 1.02(t, J=7.4 Hz, 3H).

5-Amino-3-(4-bromophenyl)-1-[1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile

Following a modified general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (100 mg, 0.38mmol) and 1-(trifluoromethyl)propylhydrazine hydrochloride (102 mg, 0.57mmol) afforded, after purification, titled compound (135 mg, 0.36 mmol,95% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 2.03 min, m/z373.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-[1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile(135 mg, 0.36 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (196 mg, 0.72 mmol)afforded, after purification, titled compound (219 mg, 0.48 mmol) as ayellow gum. UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 458.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(219 mg, 0.48 mmol) afforded, after purification, titled compound (77mg, 0.16 mmol, 34% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.62 min, m/z 476.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.69 min, m/z476.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 7.74 (dd, J=7.7,1.7 Hz, 1H), 7.49-7.39 (m, 5H), 7.14 (d, J=8.2 Hz, 1H), 7.06-7.00 (m,1H), 6.69 (s, 2H), 5.12-5.00 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.89 (s,3H), 2.27-2.16 (m, 1H), 1.99-1.88 (m, 1H), 0.79 (t, J=7.3 Hz, 3H).

Example 171:5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

N-[[2-Methyl-1-(trifluoromethyl)propylidene]amino]benzamide

Following general procedure S, 1,1,1-trifluoro-3-methyl-2-butanone (3.31mmol) and benzhydrazide (2.20 mmol) afforded titled compound (1.30 mmol)as a white solid. UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 259.0[M+H]⁺

N′-[2-Methyl-1-(trifluoromethyl)propyl]benzohydrazide

Following general procedure T,N-[[2-methyl-1-(trifluoromethyl)propylidene]amino]benzamide (335 mg,1.30 mmol) afforded titled compound (341 mg, 1.31 mmol, quantitativeyield) as a crude white solid. UPLC-MS (ES⁺, Short acidic): 1.66 min,m/z 261.0 [M+H]⁺

[2-Methyl-1-(trifluoromethyl)propyl]hydrazine hydrochloride

Following general procedure U,N′-[2-methyl-1-(trifluoromethyl)propyl]benzohydrazide (341 mg, 1.31mmol) afforded crude titled compound (243 mg, 1.26 mmol) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆, δ): 3.63-3.52 (m, 1H), 2.14-2.04 (m,1H), 1.04 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H).

5-Amino-3-(4-bromophenyl)-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile

Following a modified general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (100 mg, 0.38mmol) and [2-methyl-1-(trifluoromethyl)propyl]hydrazine hydrochloride(110 mg, 0.57 mmol) afforded, after purification, titled compound (99mg, 0.26 mmol, 67% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):2.10 min, m/z 387.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile(99 mg, 0.26 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (139 mg, 0.51 mmol)afforded, after purification, titled compound (179 mg, 0.38 mmol,assumed quantitative yield) as a yellow gum. UPLC-MS (ES⁺, Shortacidic): 1.82 min, m/z 472.1 [M+H]⁺

5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide(179 mg, 0.38 mmol) afforded, after purification, titled compound (66mg, 0.12 mmol, 32% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.69 min, m/z 490.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.89 min, m/z490.2 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d₆, δ): 8.72 (t, J=6.0 Hz, 1H), 7.74(dd, J=7.7, 1.7 Hz, 1H), 7.49-7.39 (m, 5H), 7.14 (d, J=8.2 Hz, 1H),7.05-7.00 (m, 1H), 6.68 (s, 2H), 4.90-4.80 (m, 1H), 4.54 (d, J=6.0 Hz,2H), 3.89 (s, 3H), 2.61-2.50 (m, 1H), 1.09 (d, J=6.4 Hz, 3H), 0.77 (d,J=6.6 Hz, 3H).

Example 172:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(1-tetrahydrofuran-3-ylethyl)pyrazole-4-carboxamide

N-Methoxy-N-methyl-tetrahydrofuran-3-carboxamide

A solution of tetrahydro-3-furoic acid (0.25 mL, 2.61 mmol),triethylamine (0.7 mL, 5.23 mmol), a propylphosphonic anhydride solution(50 wt % in EtOAc, 2.3 mL, 3.92 mmol) and N,O-dimethylhydroxylaminehydrochloride (382 mg, 3.92 mmol) in DCM (10 mL) was stirred for 16 h atRT to give (after work up) titled compound (416 mg, 2.61 mmol, assumedquantitative yield) as a colourless oil. ¹H NMR (400 MHz, CDCl₃, δ):4.10-4.03 (m, 1H), 3.95-3.78 (m, 3H), 3.72 (s, 3H), 3.50-3.37 (m, 1H),3.22 (s, 3H) 2.30-2.19 (m, 1H), 2.15-2.03 (m, 1H)

1-Tetrahydrofuran-3-ylethanone

To a solution of N-methoxy-N-methyl-tetrahydrofuran-3-carboxamide (276mg, 1.73 mmol) in THF (8 mL), at 0° C., was added bromo(methyl)magnesium(3.4 M in 2-MeTHF, 0.7 mL, 2.25 mmol). The reaction mixture was stirredat RT for 16 h. The reaction mixture was quenched with HCl (1 M inwater), the residue was diluted with diethyl ether, washed with water,dried over sodium sulfate and concentrated under reduced pressure toafford crude 1-tetrahydrofuran-3-ylethanone (127 mg, 1.11 mmol, 64%yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃, δ): 4.00-3.70 (m, 4H),3.27-3.18 (m, 1H), 2.23 (s, 3H), 2.17-2.09 (m, 2H).

tert-Butyl N-[1-tetrahydrofuran-3-ylethylideneamino]carbamate

Following general procedure E, 1-tetrahydrofuran-3-ylethanone (127 mg,1.11 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane, titled compound (0.60mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.26 min, m/z 229.0[M+H]⁺

5-Amino-3-(4-bromophenyl)-1-n-tetrahydrofuran-3-ylethyl)pyrazole-4-carbonitrile

Following a modified general procedure O at RT, tert-butylN-[1-tetrahydrofuran-3-ylethylideneamino]carbamate (0.38 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (95 mg, 0.36 mmol)gave, after purification by reverse-phase chromatography eluting withisocratic 30% MeCN in water containing 0.1% formic acid, titled compound(33 mg, 0.09 mmol, 26% yield) as an off-white powder. UPLC-MS (ES⁺,Short acidic): 1.81 min, m/z 361.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(1-tetrahydrofuran-3-ylethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(1-tetrahydrofuran-3-ylethyl)pyrazole-4-carbonitrile(33 mg, 0.09 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (59 mg,0.20 mmol) gave, after purification by flash column chromatrography onsilica gel eluting with 0-100% EtOAc in heptane, titled compound (37 mg,0.08 mmol, 87% yield) as an off-white powder. UPLC-MS (ES⁺, Shortacidic): 1.62 min, m/z 464.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(1-tetrahydrofuran-3-ylethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(1-tetrahydrofuran-3-ylethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(37 mg, 0.08 mmol) gave, after purification by flash columnchromatrography on silica gel eluting with 2-5% MeOH in DCM, aninseparable diastereoisomeric mixture of5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(1-tetrahydrofuran-3-ylethyl)pyrazole-4-carboxamide(12 mg, 0.02 mmol, 30% yield) as a white solid. UPLC-MS (ES⁺, Shortacidic): 1.43 min, m/z 482.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.24min, m/z 482.2 [M+H]⁺, 3.28 min, m/z 482.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ, mixture of diastereoisomers): 8.83 (t,J=6.0 Hz, 1H), 7.51 (dd, J=9.2, 3.3 Hz, 1H), 7.48-7.43 (m, 2H), 7.41 (d,J=8.2 Hz, 2H), 7.37-7.30 (m, 1H), 7.18 (dd, J=9.1, 4.3 Hz, 1H), 6.38 (s,1.34H), 6.36 (s, 0.66H), 4.54 (d, J=6.0 Hz, 2H), 4.30-4.18 (m, 1H), 3.89(s, 3H), 3.86-3.40 (m, 3.67H), 3.28-3.30 (m, 0.33H), 2.82-2.63 (m, 1H),2.10-1.91 (m, 0.33H), 1.76-1.54 (m, 1H), 1.54-1.40 (m, 0.67H), 1.34 (d,J=6.5 Hz, 1H), 1.29 (d, J=6.5 Hz, 2H).

Example 173:5-amino-1-(2,2-difluoro-1-methyl-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-(2,2-difluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2,2-difluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(91 mg, 0.27 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (170 mg,0.59 mmol) gave, after purification, titled compound (119 mg, 0.27 mmol,assumed quantitative yield) as an off-white powder. UPLC-MS (ES⁺, Shortacidic): 1.70 min, m/z 444.1 [M+H]⁺

5-Amino-1-(2,2-difluoro-1-methyl-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2-difluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(119 mg, 0.27 mmol) gave, after purification, titled compound (85 mg,0.18 mmol, 69% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.53 min, m/z 462.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.49 min, m/z462.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (t, J=6.1 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.38-7.30(m, 1H), 7.18 (dd, J=9.1, 4.3 Hz, 1H), 6.53 (s, 2H), 6.21 (dt, J=55.8,5.4 Hz, 1H), 4.85-4.70 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.89 (s, 3H),1.44 (d, J=6.7 Hz, 3H).

Example 174:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(3,3,3-trifluoropropyl)pyrazole-4-carboxamide

N-[3,3,3-Trifluoropropylideneamino]benzamide

Following general procedure S, 3,3,3-trifluoropropanal (0.15 mL, 1.78mmol) gave a cis-trans mixture ofN-[3,3,3-trifluoropropylideneamino]benzamide (290 mg, 1.26 mmol) as anoff-white solid. UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 230.9 [M+H]⁺

N′-(3,3,3-Trifluoropropyl)benzohydrazide

Following general procedure T,N-[3,3,3-trifluoropropylideneamino]benzamide (290 mg, 1.26 mmol) gavecrude N′-(3,3,3-trifluoropropyl)benzohydrazide (201 mg, 0.87 mmol, 69%yield) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z233.1[M+H]⁺

3,3,3-Trifluoropropylhydrazine hydrochloride

Following general procedure U, N-(3,3,3-trifluoropropyl)benzohydrazide(201 mg, 0.87 mmol) gave crude 3,3,3-trifluoropropylhydrazinehydrochloride (140 mg, 0.85 mmol, assumed quantitative yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆, δ): 3.07 (t, J=14.9 Hz, 2H), 2.58-2.56(m, 2H).

5-Amino-3-(4-bromophenyl)-1-(3,3,3-trifluoropropyl)pyrazole-4-carbonitrile

Following general procedure H, 3,3,3-trifluoropropylhydrazinehydrochloride (140 mg, 0.85 mmol), and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (224 mg, 0.85mmol) gave, after purification by flash column chromatography on silicagel eluting with 0-80% EtOAc in heptane, titled compound (227 mg, 0.63mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.91 min, m/z361.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3,3,3-trifluoropropyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(3,3,3-trifluoropropyl)pyrazole-4-carbonitrile(227 mg, 0.63 mmol), and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (909 mg,3.15 mmol) gave, after purification, titled compound (270 mg, 0.59mmol). UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 462.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(3,3,3-trifluoropropyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(3,3,3-trifluoropropyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(270 mg, 0.59 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-100% EtOAc in heptane,titled compound (66 mg, 0.14 mmol, 24% yield) as an off-white solid.UPLC-MS (ES⁺, Short acidic): 1.48 min, m/z 480.1 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 3.42 min, m/z 480.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (t, J=6.4 Hz, 1H), 7.50 (dd, J=9.2,3.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.36-7.28(m, 1H), 7.17 (dd, J=9.2, 4.4 Hz, 1H), 6.45 (s, 2H), 4.53 (d, J=6.1 Hz,2H), 4.18 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 2.83-2.69 (m, 2H).

Example 175:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazole-4-carboxamide

Benzyl tetrahydrofuran-3-carboxylate

A solution of tetrahydro-3-furoic acid (0.25 mL, 2.61 mmol), potassiumcarbonate (433 mg, 3.14 mmol) and benzyl bromide (0.3 mL, 2.74 mmol) inMeCN (5.5 mL) was stirred at RT for 16 h. Work up and purificationafforded titled compound (398 mg, 1.93 mmol, 74% yield) as a colourlessoil.

¹H NMR (400 MHz, CDCl₃, δ): 7.43-7.32 (m, 5H), 5.17 (s, 2H), 4.04-3.80(m, 4H), 3.21-3.11 (m, 1H), 2.30-2.10 (m, 2H)

tert-ButylN-[(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethylidene)amino]carbamate

To a solution of benzyl tetrahydrofuran-3-carboxylate (398 mg, 1.93mmol) in THF (3.8 mL), at 0° C., was addedtrimethyl(trifluoromethyl)silane (0.34 mL, 2.32 mmol) andtetrabutylammonium fluoride (1 M in THF, 0.48 mL, 0.48 mmol). Thereaction mixture was stirred at RT for 16 h, then tert-butyl carbazate(255 mg, 1.93 mmol) and acetic acid (3.8 mL) were added. The mixture washeated to 90° C. for 3 h and cooled to RT. Work up and purificationafforded titled compound (409 mg, 1.45 mmol, 75% yield) as a clear oil.UPLC-MS (ES⁻, Short acidic): 1.79 min, m/z 281.0 [M−H]⁻

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazole-4-carbonitrile

Following general procedure O, tert-butylN-[(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethylidene)amino]carbamate(409 mg, 1.45 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (120 mg, 0.46mmol) gave, after purification by flash column chromatography on silicagel eluting with 0-55% EtOAc in heptane,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazole-4-carbonitrile(98 mg, 0.24 mmol, 52% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.89 min, m/z 414.9 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazole-4-carbonitrile(98 mg, 0.24 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (149 mg,0.52 mmol) gave, after purification, titled compound (115 mg, 0.22 mmol)as an off-white powder. UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 518.1[M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(115 mg, 0.22 mmol) gave, after purification, titled compound (15 mg,0.03 mmol, 13% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 536.2 [M+H]⁺, 1.53 min, m/z536.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.51 min, m/z 536.1 [M+H]⁺, 3.56 min, m/z536.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ, mixture of diastereoisomers): 8.82 (t,J=5.9 Hz, 1H), 7.52-7.43 (m, 3H), 7.41 (d, J=7.9 Hz, 2H), 7.36-7.28 (m,1H), 7.17 (dd, J=9.1, 4.3 Hz, 1H), 6.73 (s, 0.66H), 6.71 (s, 1.34),5.26-5.12 (m, 1H), 4.53 (d, J=6.0 Hz, 2H), 3.94-3.82 (m, 4H), 3.76-3.67(m, 1H), 3.65-3.57 (m, 1H), 3.57-3.50 (m, 0.33H), 3.25-3.03 (m, 1.67H),2.18-2.04 (m, 0.67H), 1.86-1.71 (m, 1H), 1.54-1.40 (m, 0.33H)

Example 176:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(3,3,3-trifluoro-2-methyl-propyl)pyrazole-4-carboxamide

N-[(3,3,3-Trifluoro-2-methyl-propylidene)amino]benzamide

Following general procedure S, 3,3,3-trifluoro-2-methylpropanal (200 mg,1.59 mmol), gave after purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptaneN-[(3,3,3-trifluoro-2-methyl-propylidene)amino]benzamide (164 mg, 0.67mmol, 42% yield) as a mixture of diastereoisomers. UPLC-MS (ES⁺, Shortacidic): 1.45 min, m/z 245.0 [M+H]⁺

N′-(3,3,3-Trifluoro-2-methyl-propyl)benzohydrazide

Following general procedure T,N-[(3,3,3-trifluoro-2-methyl-propylidene)amino]benzamide (164 mg, 0.67mmol) gave crude N′-(3,3,3-trifluoro-2-methyl-propyl)benzohydrazide (160mg, 0.65 mmol) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.51 min,m/z 247.1 [M+H]⁺

(3,3,3-Trifluoro-2-methyl-propyl)hydrazine hydrochloride

Following general procedure U,N-(3,3,3-trifluoro-2-methyl-propyl)benzohydrazide (160 mg, 0.65 mmol)gave (3,3,3-trifluoro-2-methyl-propyl)hydrazine hydrochloride (0.65mmol) as a white solid.

¹H NMR (400 MHz, DMSO-d₆, δ): 3.17-3.14 (m, 1H), 2.82-2.76 (m, 2H), 1.10(d, J=6.5 Hz, 3H)

5-Amino-3-(4-bromophenyl)-1-(3,3,3-trifluoro-2-methyl-propyl)pyrazole-4-carbonitrile

General procedure H, (3,3,3-trifluoro-2-methyl-propyl)hydrazinehydrochloride (0.65 mmol), and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.65 mmol) gave,after purification, the titled compound (0.34 mmol) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 2.01 min, m/z 375.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3,3,3-trifluoro-2-methyl-propyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(3,3,3-trifluoro-2-methyl-propyl)pyrazole-4-carbonitrile(130 mg, 0.34 mmol), and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (490 mg,1.71 mmol) gave, after purification, the titled compound (0.26 mmol) asan off-white solid. UPLC-MS (ES⁺, Short acidic): 1.81 min, m/z 476.1[M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(3,3,3-trifluoro-2-methyl-propyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(3,3,3-trifluoro-2-methyl-propyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(127 mg, 0.27 mmol) gave, after purification, titled compound (31 mg,0.06 mmol, 23% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 494.1 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 3.61 min, m/z 494.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (t, J=6.0 Hz, 1H), 7.49 (dd, J=9.2,3.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.36-7.28(m, 1H), 7.17 (dd, J=9.2, 4.4 Hz, 1H), 6.47 (s, 2H), 4.53 (d, J=6.0 Hz,2H), 4.16 (dd, J=14.2, 9.6 Hz, 1H), 4.05 (dd, J=14.2, 8.8 Hz, 1H), 3.87(s, 3H), 3.06-2.92 (m, 1H), 1.02 (d, J=6.8 Hz, 3H).

Example 177:5-amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromo-3-fluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromo-3-fluoro-phenyl)-methoxy-methylene]propanedinitrile (130 mg,0.46 mmol) and (2,2,2-trifluoro-1-methyl-ethyl)hydrazine hydrochloride(100 mg, 0.61 mmol) afforded, after purification, titled compound (153mg, 0.41 mmol, 88% yield) as white solid.

UPLC-MS (ES+, Short acidic): 2.01 min, m/z 378.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromo-3-fluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(147 mg, 0.39 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (225 mg,0.78 mmol) gave crude titled compound (0.39 mmol) as a light yellowsolid. UPLC-MS (ES+, Short acidic): 1.86 min, m/z 480.0 [M+H]⁺

5-Amino-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(230 mg, 0.48 mmol) gave, after purification, titled compound (73 mg,0.15 mmol, 31% yield) as a pale yellow solid. UPLC-MS (ES+, Shortacidic): 1.58 min, m/z 498.1 [M+H]⁺ UPLC-MS (ES+, Long acidic): 3.69min, m/z 498.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (t, J=6.0 Hz, 1H), 7.49 (dd, J=9.2,3.2 Hz, 1H), 7.45-7.26 (m, 4H), 7.18 (dd, J=9.1, 4.3 Hz, 1H), 6.60 (s,2H), 5.34-5.23 (m, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 1.60 (d,J=6.9 Hz, 3H).

Example 178:5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-phenyl-ethyl)pyrazole-4-carboxamide

N-[(2,2,2-Trifluoro-1-phenyl-ethylidene)amino]benzamide

Following general procedure S, 2,2,2-trifluoroacetophenone (33.0 mmol)and benzhydrazide (22.0 mmol) gave, after purification, titled compound(3.44 mmol) as a white solid. UPLC-MS (ES+, Short acidic): 1.82 min, m/z293.0 [M+H]⁺

N′-(2,2,2-Trifluoro-1-phenyl-ethyl)benzohydrazide

Following general procedure T,N-[(2,2,2-trifluoro-1-phenyl-ethylidene)amino]benzamide (997 mg, 3.41mmol) in THF (15 mL) gaveN′-(2,2,2-trifluoro-1-phenyl-ethyl)benzohydrazide (1.01 g, 3.43 mmol) asa yellow solid. UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 295.0 [M+H]⁺

(2,2,2-Trifluoro-1-phenyl-ethyl)hydrazine hydrochloride

Following general procedure U,N′-(2,2,2-trifluoro-1-phenyl-ethyl)benzohydrazide (996 mg, 3.38 mmol)gave titled compound (628 mg, 2.77 mmol) as a white solid. ¹H NMR (400MHz, DMSO-d₆, δ): 9.67 (s, 3H), 7.53-7.46 (m, 5H), 6.63 (d, J=6.4 Hz,1H), 5.10-5.02 (m, 1H)

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-phenyl-ethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (200 mg, 0.76mmol) and (2,2,2-trifluoro-1-phenyl-ethyl)hydrazine hydrochloride (621mg, 0.96 mmol) afforded, after purification, titled compound (266 mg,0.63 mmol, 83% yield) was obtained as white solid. UPLC-MS (ES⁺, Shortacidic): 2.06 min, m/z 422.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-phenyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-phenyl-ethyl)pyrazole-4-carbonitrile(261 mg, 0.62 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (358 mg,1.24 mmol) gave, after purification, titled compound (73 mg, 0.14 mmol,23% yield) as a white solid. UPLC-MS (ES+, Short acidic): 1.85 min, m/z524.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-phenyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-phenyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(71 mg, 0.14 mmol) gave, after purification, titled compound (62 mg,0.12 mmol, 84% yield) as a white solid. UPLC-MS (ES+, Short acidic):1.71 min, m/z 542.1 [M+H]⁺ UPLC-MS (ES+, Long acidic): 4.06 min, m/z542.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.85 (t, J=6.1 Hz, 1H), 7.72-7.70 (m, 2H),7.52-7.41 (m, 8H), 7.35-7.30 (m, 1H), 7.19-7.16 (m, 1H), 6.79 (s, 2H),6.51-6.45 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.88 (s, 3H).

Example 179:5-amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

5-Amino-3-(4-bromo-2-fluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

Following general procedure H at RT,2-[(4-bromo-2-fluoro-phenyl)-methoxy-methylene]propanedinitrile (100 mg,0.38 mmol) and (2,2,2-trifluoro-1-methyl-ethyl)hydrazine hydrochloride(88 mg, 0.53 mmol) afforded, after purification, titled compound (120mg, 0.32 mmol, 84% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.84 min, m/z 378.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromo-2-fluoro-phenyl)-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carbonitrile(120 mg, 0.32 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (184 mg,0.64 mmol) afforded, after purification, titled compound (126 mg, 0.26mmol, 83% yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.69min, m/z 480.0 [M+H]⁺

5-Amino-3-[2-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]-3-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(126 mg, 0.26 mmol) afforded, after purification, titled compound (97mg, 0.17 mmol, 66% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.54 min, m/z 498.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.56 min, m/z498.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.88 (t, J=6.1 Hz, 1H), 7.48 (dd, J=9.1,3.2 Hz, 1H), 7.41-7.30 (m, 2H), 7.27-7.21 (m, 2H), 7.20-7.16 (m, 1H),6.62 (s, 2H), 5.34-5.24 (m, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.88 (s, 3H),1.58 (d, J=6.8 Hz, 3H).

Example 180:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile(102 mg, 0.26 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (152 mg,0.53 mmol) afforded, after purification, titled compound (69 mg, 0.14mmol, 54% yield) as a yellow gum. UPLC-MS (ES⁺, Short acidic): 1.89 min,m/z 490.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[2-methyl-1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(69 mg, 0.14 mmol) afforded, after purification, titled compound (22 mg,0.04 mmol, 31% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.66 min, m/z 508.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.91 min, m/z508.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (t, J=6.0 Hz, 1H), 7.53-7.39 (m, 5H),7.36-7.29 (m, 1H), 7.20-7.15 (m, 1H), 6.68 (s, 2H), 4.90-4.80 (m, 1H),4.53 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 2.61-2.52 (m, 1H), 1.09 (d, J=6.4Hz, 3H), 0.77 (d, J=6.6 Hz, 3H).

Example 181:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

N-[[4-[5-Amino-4-cyano-1-[1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile(123 mg, 0.33 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (190 mg,0.66 mmol) afforded, after purification, titled compound (101 mg, 0.21mmol, 65% yield) as a yellow gum.

UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 476.1 [M+H]⁺

5-Amino-3-[4-[[5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[1-(trifluoromethyl)propyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(101 mg, 0.21 mmol) afforded, after purification, titled compound (32mg, 0.06 mmol, 28% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.59 min, m/z 494.1 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.71 min, m/z494.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (t, J=6.0 Hz, 1H), 7.53-7.38 (m, 5H),7.37-7.27 (m, 1H), 7.20-7.14 (m, 1H), 6.69 (s, 2H), 5.12-5.00 (m, 1H),4.53 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 2.28-2.14 (m, 1H), 2.01-1.87 (m,1H), 0.79 (t, J=7.3 Hz, 3H).

Example 182:5-amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Tetrahydrofuran-3-ylhydrazine hydrochloride

To a solution of 3-hydroxytetrahydrofuran (2.8 mL, 34.0 mmol) in toluene(40 mL), under nitrogen, was added triphenylphosphine (13.4 g, 51.1mmol) and di-tert-buty 1 azodicarboxylate (9.4 g, 40.9 mmol). Thereaction mixture was stirred at RT for 60 h. The reaction mixture wasconcentrated then suspended in MeOH (100 mL), followed by addition of ahydrogen chloride solution (4 M in dioxane, 68.1 mL, 272.4 mmol). Thereaction mixture was stirred at RT for 16 h, filtered, and the filtratewas concentrated under reduced pressure. EtOAc was then added to theresidue, filtered and washed with EtOAc to afford crude titled compound(6.7 g, 48.1 mmol) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆, δ):3.91-3.61 (m, 5H), 2.12-1.86 (m, 2H).

5-Amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

A modified general procedure H at RT,2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile(0.59 mmol) and tetrahydrofuran-3-ylhydrazine hydrochloride (0.88 mmol)afforded, after purification, the titled compound (0.18 mmol) as ayellow gum.

UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z 325.0 [M]⁺

N-[[4-(5-Amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-chloro-2,3-difluoro-phenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile(60 mg, 0.18 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (159 mg,0.55 mmol) afforded, after purification, the titled compound (0.18 mmol)as a yellow gum. UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 472.1 [M+H]⁺

5-Amino-3-[2,3-difluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)-2,3-difluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(94 mg, 0.20 mmol) afforded, after purification, the titled compound (26mg, 0.05 mmol, 24% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 490.1 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 3.23 min, m/z 490.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.86 (t, J=6.0 Hz, 1H), 7.51-7.47 (m, 1H),7.38-7.30 (m, 1H), 7.25-7.15 (m, 3H), 6.32 (s, 2H), 4.97-4.90 (m, 1H),4.58 (d, J=6.0 Hz, 2H), 4.00-3.86 (m, 5H), 3.81-3.75 (m, 2H), 2.28-2.18(m, 2H).

Example 183:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(3R)-tetrahydropyran-3-yl]pyrazole-4-carboxamide

[(3S)-Tetrahydropyran-3-yl]hydrazine

To a solution of (A)-tetrahydro-2H-pyran-3-ol (0.46 mL, 4.9 mmol) intoluene (9 mL) was added triphenylphosphine (1.93 g, 7.34 mmol) anddi-tert-butylazodicarboxylate (1.35 g, 5.87 mmol). The reaction mixturewas stirred at RT under nitrogen for 16 h. The reaction mixture wasconcentrated and MeOH (21 mL) was added followed by a hydrogen chloridesolution (4 M in dioxane, 9.8 mL, 39.17 mmol). The reaction mixture wasstirred at RT for 16 h. The reaction mixture was then filtered and thefiltrate was concentrated under reduced pressure. The resulting residuewas then recrystalised from EtOAc, purified by SCX column eluting withNEE (7 M solution in MeOH), and concentrated under reduced pressure togive crude [(3R)-tetrahydropyran-3-yl]hydrazine (0.09 g, 0.77 mmol, 16%yield) as a yellow oil.

¹H NMR (400 MHz, DMSO-d₆, δ): 3.90-3.82 (m, 1H), 3.71-3.61 (m, 1H),3.34-3.22 (m, 1H), 3.13-3.04 (m, 1H), 2.65-2.50 (m, 1H), 1.90-1.77 (m,1H), 1.69-1.55 (m, 1H), 1.51-1.35 (m, 1H), 1.33-1.20 (m, 1H).

5-Amino-3-(4-bromophenyl)-1-[(3R)-tetrahydropyran-3-yl]pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (166 mg, 0.63mmol), and [(3R)-tetrahydropyran-3-yl]hydrazine (88 mg, 0.76 mmol) gave,after purification, titled compound (110 mg, 0.32 mmol, 42% yield).UPLC-MS (ES+, Short acidic): 1.76 min, 347.0 m/z [M]⁺

N-[[4-[5-Amino-4-cyano-1-[(3R)-tetrahydropyran-3-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (210 mg,0.73 mmol), and5-amino-3-(4-bromophenyl)-1-[(3R)-tetrahydropyran-3-yl]pyrazole-4-carbonitrile(150 mg, 0.43 mmol) gave, after purification, titled compound (0.25mmol) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.60 min,450.1 m/z [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(3R)-tetrahydropyran-3-yl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[(3R)-tetrahydropyran-3-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(112 mg, 0.25 mmol) gave, after purification, titled compound (29 mg,0.06 mmol, 25% yield) as a white solid. UPLC-MS (ES+, Short acidic):1.39 min, 468.1 m/z [M+H]⁺ UPLC-MS (ES+, Long acidic): 3.19 min, 468.1m/z [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.1 Hz, 1H), 7.52 (dd, J=9.2,3.3 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.38-7.30(m, 1H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 6.22 (s, 2H), 4.55 (d, J=6.1 Hz,2H), 4.22-4.14 (m, 1H), 4.00-3.96 (m, 2H), 3.90 (s, 3H), 3.83-3.76 (m,1H), 3.67-3.60 (m, 1H), 1.99-1.87 (m, 1H), 1.87-1.74 (m, 2H), 1.74-1.61(m, 1H).

Example 184:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)pyrazole-4-carboxamide

N-[(2,2,2-Trifluoro-1-tetrahydropyran-4-yl-ethylidene)amino]benzamide

A mixture of magnesium (1.2 g, 45.4 mmol) and iodine (23 mg, 0.09 mmol)in THF (7 mL) was heated to 60° C. Following activation, the mixture wascooled to RT and a solution 4-bromotetrahydro-2H-pyran (1.02 mL, 9.09mmol) in THF (2 mL) was added dropwise. The mixture was heated to refluxfor 1 h, and then cooled to RT. The preformed reagent was then added toa solution of N-methoxy-N-methyltrifluoroacetamide (0.82 mL, 6.82 mmol)in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1h, quenched with saturated aqueous solution of NH₄Cl and partitionedwith diethyl ether. The aqueous layer was extracted with Et₂O. Thecombined organic layers were dried over sodium sulfate, filtered andEt₂O was removed under reduced pressure to give a THF solution of2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethanone (assumed quantitativeyield). Following general procedure S, the previously prepared solutionof benzhydrazide and 2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethanone(0.15 mL, 9.09 mmol) gave, after 48 h and further purification by flashcolumn chromatography on silica gel eluting with 0-100% EtOAc inheptane,N-[(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethylidene)amino]benzamide(300 mg, 1.00 mmol, 11% yield).

UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 301.0 [M+H]⁺

N′-(2,2,2-Trifluoro-1-tetrahydropyran-4-yl-ethyl)benzohydrazide

Following general procedure T,N-[(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethylidene)amino]benzamide(403 mg, 1.34 mmol) gave, after purification, titled compound (168 mg,0.56 mmol, 41% yield). UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 303.0[M+H]⁺

(2,2,2-Trifluoro-1-tetrahydropyran-4-yl-ethyl)hydrazine hydrochloride

Following procedure U,N-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)benzohydrazide (168 mg,0.56 mmol) gave, after 48 h, (titled compound (85 mg, 0.36 mmol, 65%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, δ): 3.91-3.83 (m,2H), 3.72-3.61 (m, 1H), 3.35-3.22 (m, 2H), 2.07-1.95 (m, 1H), 1.67-1.52(m, 3H), 1.50-1.36 (m, 1H).

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)pyrazole-4-carbonitrile

Following a modified general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (80 mg, 0.30 mmol)and (2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)hydrazinehydrochloride (85 mg, 0.36 mmol) afforded crude titled compound (146 mg,0.34 mmol, assumed quantitative yield).

UPLC-MS (ES⁺, Short acidic) 1.93 min, m/z 428.9 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)pyrazole-4-carbonitrile(130 mg, 0.30 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (193 mg,0.67 mmol) gave crude titled compound (160 mg, 0.30 mmol, quantitativeyield).

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 532.2 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-tetrahydropyran-4-yl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(160 mg, 0.30 mmol) afforded, after purification by flash columnchromatography on silica gel eluting with 0-6% MeOH in DCM and furtherpurification by mass directed semi-preparative HPLC, titled compound(0.02 mmol). UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 550.2 [M+H]⁺UPLC-MS (ES⁺, Long acidic): 3.61 min, m/z 550.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (t, J=6.1 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.48-7.40 (m, 4H), 7.37-7.30 (m, 1H), 7.19 (dd, J=9.2, 4.3Hz, 1H), 6.71 (br s, 2H), 5.06-4.98 (m, 1H), 4.55 (d, J=6.1 Hz, 2H),3.89 (s, 3H), 3.89-3.77 (m, 2H), 3.37-3.22 (m, 2H), 2.68-2.42 (m, 1H),1.81-1.17 (m, 1H), 1.54-1.43 (m, 1H), 1.34-1.21 (m, 1H), 1.10-1.01 (m,1H).

Example 185:5-amino-1-cyclopentyl-3-[4-[2-hydroxy-1-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]pyrazole-4-carboxamide

2-Bromo-1-(4-bromo-2-methyl-phenyl)ethanone

To a solution of 1-(4-bromo-2-methylphenyl)ethanone (2.0 g, 9.39 mmol)in MeCN (40 mL) was added N-bromosuccinimide (1.7 g, 9.57 mmol) andp-toluenesulfonic acid monohydrate (1.8 g, 9.39 mmol). The reaction wasstirred at 50° C. for 18 h, concentrated and after work-up afforded thetitled compound (9.39 mmol).

UPLC-MS (ES⁺, Short acidic): 1.91 min, m/z 292.8 [M+H]⁺

1-(4-Bromo-2-methyl-phenyl)-2-hydroxy-ethanone

To a solution of 2-bromo-1-(4-bromo-2-methyl-phenyl)ethanone (9.4 mmol)in MeOH (30 mL) was added cesium formate hydrate (28.2 mmol) and thesolution was stirred at 80° C. for 4 h. Following work-up the titledcompound was afforded (10.3 mmol). UPLC-MS (ES⁺, Short acidic): 1.53min, m/z 230.8 [M+2]⁺

1-(4-Bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanone

To a solution of 1-(4-bromo-2-methyl-phenyl)-2-hydroxy-ethanone (2.15 g,9.39 mmol) in DCM (30 mL) was added imidazole (959 mg, 14.1 mmol). Thesolution was cooled to 0° C. followed by dropwise addition oftert-butyl-chlorodimethylsilane (2.00 mL, 14.1 mmol) in DCM (10 mL). Thesolution was then stirred at 0° C. for 30 min then stirred at RT for 18h. Work up and purification afforded titled compound (2.22 g, 6.47 mmol)as a colourless oil.

UPLC-MS (ES⁺, Short acidic): 2.43 min, m/z 345.0 [M+2]⁺

1-(4-Bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanol

Sodium borohydride (32.3 mmol) was added to a solution of1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanone(6.47 mmol) in MeOH (20 mL) at 0° C. The reaction was stirred at 0° C.for 1 h then stirred at RT for 3.5 h. Work up and purification gavetitled compound (6.26 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 7.40-7.38 (m, 1H), 7.33-7.36 (m, 1H),7.28-7.29 (m, 1H), 4.89-4.95 (m, 1H), 3.75-3.68 (m, 1H), 3.50-3.40 (m,1H), 2.33-2.27 (m, 3H), 0.92 (s, 9H), 0.07 (s, 6H).

2-[1-(4-Bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione

Phthalimide (1.06 g, 7.20 mmol) and triphenylphosphine (1.89 g, 7.20mmol) was added to1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanol(2.16 g, 6.26 mmol) in THF (10 mL) at 0° C. A solution of diisopropylazodicarboxylate (1.4 mL, 7.20 mmol) in THF (10 mL) was added dropwiseto the reaction. The reaction was stirred at 0° C. for 30 min thenstirred at RT for 66 h. Work up and purification by flash columnchromatography on silica gel eluting with 0-20% EtOAc in heptaneafforded2-[1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione(1.55 g, 3.26 mmol, 52% yield) as a yellow oil, and2-[2-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione(901 mg, 1.90 mmol, 30% yield) as a white solid.

2-[1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione

UPLC-MS (ES⁻, Short acidic): 2.50 min, m/z 476.0 [M+2]⁺

2-[2-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione

UPLC-MS (ES⁺, Short acidic): 2.48 min, m/z 476.1 [M+2]⁺

2-[1-(4-Bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione

Hydrazine hydrate (55-60% in water, 0.26 mL, 5.27 mmol) was addeddropwise to a solution of2-[1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione(500 mg, 1.05 mmol) in EtOH (5 mL). The reaction was heated to 80° C.for 1.5 h, cooled to RT and filtered. The filtrate was concentratedunder reduced pressure and purification by SCX eluting with 1 M NH₃ inMeOH afforded titled compound (243 mg, 0.70 mmol, 67% yield).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.43 (d, J=8.1 Hz, 1H), 7.31-7.36 (m, 2H),4.11 (dd, J=6.9, 5.6 Hz, 1H), 3.44-3.56 (m, 2H), 2.29 (s, 3H), 0.81 (s,9H), −0.05 (s, 3H), −0.06 (s, 3H),

N-[1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]-2-methoxy-benzamide

To a solution of1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanamine(0.710 mmol) in THF (3 mL) was added N,N-diisopropylethylamine (2.12mmol). 2-Methoxybenzoyl chloride (0.78 mmol) was added to the reactionat 0° C. The reaction was stirred at 0° C. for 20 min then stirred at RTfor 66 h and quenched with saturated aqueous solution of NH₄Cl. Work-upand purification afforded titled compound (0.38 mmol). UPLC-MS (ES⁺,Short acidic): 2.44 min, m/z 480.1 [M+2]⁺

N-[2-[tert-Butyl(dimethyl)silyl]oxy-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-2-methoxy-benzamide

Following general procedure R,N-[1-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]-2-methoxy-benzamide(183 mg, 0.38 mmol) gave, after purification, the titled compound (146mg, 0.28 mmol, 73% yield).

UPLC-MS (ES⁺, Short acidic): 2.51 min, m/z 526.3 [M+H]⁺

5-Amino-3-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]-1-cyclopentyl-pyrazole-4-carboxamide

Following general procedure D,N-[2-[tert-butyl(dimethyl)silyl]oxy-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-2-methoxy-benzamide(150 mg, 0.29 mmol) and5-amino-3-bromo-1-cyclopentyl-pyrazole-4-carboxamide (74 mg, 0.27 mmol)afforded, following further purification, the titled compound (0.27mmol). UPLC-MS (ES⁺, Short acidic): 2.25 min, m/z 592.3 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[2-hydroxy-1-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]pyrazole-4-carboxamide

A tetrabutylammonium fluoride solution (1 M in THF, 84 μL, 0.291 mmol)was added dropwise to a solution of5-amino-3-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]-1-cyclopentyl-pyrazole-4-carboxamide(0.27 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at 0° C.for 3 h then partitioned between DCM and water. The organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. Further purification by flash columnchromatography on silica gel eluting with 0-5% MeOH in DCM followed bymass-directed semi-preparative HPLC afforded titled compound (0.06mmol). UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 478.1 [M+H]⁺ UPLC-MS(ES⁺, Long acidic): 3.29 min, m/z 478.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.69 (d, J=7.6 Hz, 1H), 7.73 (dd, J=7.6,1.9 Hz, 1H), 7.52-7.46 (m, 1H), 7.42-7.39 (m, 1H), 7.30-7.25 (m, 2H),7.18 (d, J=8.4 Hz, 1H), 7.08-7.01 (m, 1H), 6.33 (s, 2H), 5.32-5.23 (m,1H), 5.03 (t, J=5.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.95 (s, 3H), 3.71-3.58(m, 2H), 2.45 (s, 3H), 2.01-1.84 (m, 4H), 1.83-1.72 (m, 2H), 1.63-1.52(m, 2H).

Example 186:5-amino-1-(3,3-difluoro-4-piperidyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

tert-Butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate

Di-tert-butyl dicarbonate (1.19 g, 5.44 mmol) was added to a solution of1-benzyl-3,3-difluoropiperidin-4-one (995 mg, 4.42 mmol) in EtOH (60 mL)under nitrogen. Palladium hydroxide (Pd 20% on carbon, 148 mg, 1.05mmol) was added and the system was evacuated and flushed with hydrogenseveral times. The mixture was stirred at RT for 20 h under hydrogen.The residual hydrogen was removed and the mixture was filtered overCelite®, and washed with EtOH. Purification gave titled compound (810mg, 3.44 mmol, 78% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆, δ): 3.66-3.52 (m, 2H), 3.39-3.33 (m, 2H),1.69-1.64 (m, 2H), 1.38 (s, 9H)

tert-Butyl 4-(benzoylhydrazono)-3,3-difluoro-piperidine-1-carboxylate

Following general procedure S, tert-butyl3,3-difluoro-4-oxo-piperidine-1-carboxylate (650 mg, 2.76 mmol) intoluene (2 mL) and benzhydrazide (300 mg, 2.20 mmol) gave, afterpurification, titled compound (2.00 mmol) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.63 min, m/z 354.1 [M+H]⁺

tert-Butyl 4-(2-benzoylhydrazino)-3,3-difluoro-piperidine-1-carboxylate

Following general procedure T, tert-butyl4-(benzoylhydrazono)-3,3-difluoro-piperidine-1-carboxylate (250 mg, 0.71mmol) gave crude b titled compound (265 mg, 0.75 mmol, assumedquantitative yield) as colourless oil. UPLC-MS (ES⁺, Short acidic): 1.62min, m/z 356.1 [M+H]⁺

(3,3-Difluoro-4-piperidyl)hydrazine dihydrochloride

Following general procedure U, tert-butyl4-(2-benzoylhydrazino)-3,3-difluoro-piperidine-1-carboxylate (0.73 mmol)gave, after washing with hot EtOAc, the titled compound as a pale yellowsolid.

¹H NMR (400 MHz, DMSO-d₆, δ): 5.97 (m, 1H), 3.68-3.45 (m, 3H), 3.23-3.17(m, 1H), 3.10-3.01 (m, 1H), 2.27-2.20 (m, 1H), 1.90-1.80 (m, 1H).

5-Amino-3-(4-bromophenyl)-1-(3,3-difluoro-4-piperidyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (160 mg, 0.61mmol) and (3,3-difluoro-4-piperidyl)hydrazine dihydrochloride (170 mg,0.76 mmol) were stirred for 2 h at 85° C. Work-up and purificationafforded the titled compound (126 mg, 0.33 mmol, 54% yield) as a redsolid. UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 383.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(3,3-difluoro-4-piperidyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(3,3-difluoro-4-piperidyl)pyrazole-4-carbonitrile(121 mg, 0.32 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (158 mg,0.55 mmol) gave, after purification, the titled compound (99 mg, 0.20mmol, 65% yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.29min, m/z 485.1 [M+H]⁺

5-Amino-1-(3,3-difluoro-4-piperidyl)-3-[4-[[5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(3,3-difluoro-4-piperidyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(89 mg, 0.18 mmol) gave, after purification, the titled compound (64 mg,0.13 mmol, 69% yield) as a light yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 503.2 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 2.54 min, m/z 503.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.0 Hz, 1H), 7.52 (dd, J=9.2,3.3 Hz, 1H), 7.48-7.41 (m, 4H), 7.37-7.32 (m, 1H), 7.19 (dd, J=9.2, 4.3Hz, 1H), 6.42 (s, 2H), 4.86-4.75 (m, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.90(s, 3H), 3.30-3.21 (m, 1H), 3.14-3.11 (m, 1H), 2.99-2.88 (m, 1H),2.69-2.64 (m, 1H), 2.43-2.36 (m, 1H), 1.95-1.89 (m, 1H).

Example 187:5-amino-1-cyclopentyl-3-[4-[1-hydroxy-2-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]pyrazole-4-carboxamide

2-(4-Bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanamine

Hydrazine hydrate (55-60% in water, 0.26 mL, 5.27 mmol) was addeddropwise to a solution of2-[2-(4-bromo-2-methyl-phenyl)-2-[/t7V-butyl(dimethyl)silyl]oxy-ethyl]isoindoline-1,3-dione(500 mg, 1.05 mmol) in EtOH (5 mL). The reaction was heated to 80° C.for 1.5 h, cooled to RT, filtered and concentrated under reducedpressure to crude titled compound (324 mg, 0.94 mmol, 89% yield).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.39-7.33 (m, 2H), 7.28 (d, J=8.3 Hz, 1H),4.73 (dd, J=7.5, 3.9 Hz, 1H), 2.59 (dd, J=13.0, 3.9 Hz, 1H), 2.51-2.40(m, 1H), 2.28 (s, 3H), 0.84 (s, 9H), 0.04 (s, 3H), −0.13 (s, 3H).

N-[2-(4-Bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]-2-methoxy-benzamide

To a solution of2-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethanamine(324 mg, 0.94 mmol) in THF (5 mL) was added N,N-diisopropylethylamine(0.5 mL, 2.82 mmol). The reaction mixture was cooled down to 0° C.followed by addition of 2-methoxybenzoyl chloride (0.15 mL, 1.04 mmol).The reaction was stirred at 0° C. for 20 min then stirred at RT for 66h. Work up and purification afforded the titled compound (0.61 mmol).UPLC-MS (ES⁺, Short acidic): 2.47 min, m/z 480.1 [M+2]⁺

N-[2-[tert-Butyl(dimethyl)silyl]oxy-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-2-methoxy-benzamide

Following general procedure R,N-[2-(4-bromo-2-methyl-phenyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]-2-methoxy-benzamide(293 mg, 0.61 mmol) afforded, following purification, titled compound(286 mg, 0.54 mmol, 89% yield). UPLC-MS (ES⁺, Short acidic): 2.51 min,m/z 526.3 [M+H]⁺

5-Amino-3-[4-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]-1-cyclopentyl-pyrazole-4-carboxamide

Following general procedure D,N-[2-[tert-butyl(dimethyl)silyl]oxy-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-2-methoxy-benzamide(0.54 mmol) afforded, after purification, titled compound (0.43 mmol,77% yield). UPLC-MS (ES⁺, Short acidic): 2.24 min, m/z 592.3 [M+H]⁺

5-Amino-1-cyclopentyl-3-[4-[1-hydroxy-2-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]pyrazole-4-carboxamide

A tetrabutylammonium fluoride solution (1 M in THF, 0.14 mL, 0.480 mmol)was added dropwise to a solution of 5-amino-3-[4-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methoxybenzoyl)amino]ethyl]-3-methyl-phenyl]-1-cyclopentyl-pyrazole-4-carboxamide(256 mg, 0.43 mmol) in THF (2 mL) at 0° C. The reaction was stirred for3 h before being allowed to warm to RT and partitioned between DCM andwater. Work-up and purification afforded titled compound (103 mg, 0.22mmol, 50% yield). UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 478.1[M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.39 min, m/z 478.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.34 (t, J=5.7 Hz, 1H), 7.86 (dd, J=7.8,1.7 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.31 (d, J=8.0Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.05 (t, J=7.3 Hz, 1H),6.33 (s, 2H), 5.55 (d, J=4.3 Hz, 1H), 5.03-4.96 (m, 1H), 4.65-4.55 (m,1H), 3.89 (s, 3H), 3.69-3.60 (m, 1H), 3.31-3.23 (m, 1H), 2.38 (s, 3H),2.02-1.84 (m, 4H), 1.84-1.72 (m, 2H), 1.64-1.52 (m, 2H).

Example 188:5-amino-1-(1-cyclopropyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[2,2,2-Trifluoroethylideneamino]benzamide

To a solution of 2,2,2-trifluoro-1-methoxy-ethanol (0.74 mL, 7.69 mmol)in EtOH (26 mL) was added benzhydrazide (1.26 g, 9.23 mmol) andmolecular sieve. The reaction mixture was heated to 80° C. for 16 h.Filtration through a pad of Celite® and purification gave the titledcompound (1.16 g, 5.35 mmol, 70% yield) as a white solid. UPLC-MS (ES⁺,Short acidic): 1.39 min, m/z 216.9 [M+H]⁺

N′-(1-Cyclopropyl-2,2,2-trifluoro-ethyl)benzohydrazide

To a solution of N-[2,2,2-trifluoroethylideneamino]benzamide (2.31 mmol)in THF (15 mL) at 0° C. was added a cyclopropylmagnesium bromidesolution (0.5 M in THF, 10 mL). The reaction was stirred at RT for 16 h.Additional cyclopropylmagnesium bromide solution (0.5 M in THF, 10 mL)was added and the reaction was stirred for another 5 h. The reaction wasquenched with a saturated aqueous solution of NH₄Cl and extracted withEtOAc. Work-up and purification afforded titled compound (508 mg, 1.97mmol, 85% yield) as a yellow oil. LC-MS (ES⁺, Short acidic): 5.17 min,m/z 259.2 [M+H]⁺

(1-Cyclopropyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride

To a solution of hydrochloric acid (12 M in water, 5.0 mL, 60 mmol) wasadded N′-(1-cyclopropyl-2,2,2-trifluoro-ethyl)benzohydrazide (507 mg,1.96 mmol). The reaction mixture was stirred at 80° C. for 16 h. Thevolatiles were removed under reduced pressure and the residue taken upin EtOAc. The solid was filtered and washed with EtOAc to give crude(1-cyclopropyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride (149 mg,0.78 mmol, 40% yield) as a brown solid.

¹H NMR (400 MHz, CDCl₃, δ): 3.09-3.02 (m, 1H), 0.94-0.85 (m, 1H),0.71-0.59 (m, 3H), 0.47-0.40 (m, 1H).

5-Amino-3-(4-bromophenyl)-1-n-cyclopropyl-2,2,2-trifluoro-ethyl)pyrazole-4-carbonitrile

Modified general procedure H at RT,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.57 mmol) and(1-cyclopropyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride (0.78 mmol)gave, after purification, titled compound (0.21 mmol) as a white solid.UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 386.9 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

General procedure K,5-amino-3-(4-bromophenyl)-1-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrazole-4-carbonitrile(50 mg, 0.13 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (83 mg,0.29 mmol) gave, after purification, the titled compound (40 mg, 0.08mmol, 63% yield) as a beige solid. LC-MS (ES⁺, Short acidic): 5.79 min,m/z 488.1 [M+H]⁺

5-Amino-1-(1-cyclopropyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(40 mg, 0.08 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-20% MeOH in DCM,5-amino-1-(1-cyclopropyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(31 mg, 0.06 mmol, 76% yield) as a beige solid.

UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 528.2 [M+Na]⁺

UPLC-MS (ES⁺, Long acidic): 3.76 min, m/z 506.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (t, J=6.0 Hz, 1H), 7.50 (dd, J=9.2,3.3 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.36-7.31(m, 1H), 7.18 (dd, J=9.2, 4.2 Hz, 1H), 6.57 (s, 2H), 4.55 (d, J=6.0 Hz,2H), 4.52-4.46 (m, 1H), 3.89 (s, 3H), 1.70-1.60 (m, 1H), 0.86-0.76 (m,1H), 0.62-0.52 (m, 2H), 0.41-0.32 (m, 1H).

Example 189:5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazole-4-carboxamide

N-(Isopropylideneamino)benzamide

Following general procedure S, anhydrous acetone (0.19 mL, 2.58 mmol)gave, without further purification, N-(isopropylideneamino)benzamide(450 mg, 2.55 mmol, 99% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.06 min, m/z 177.0 [M+H]⁺

N′-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)benzohydrazide

Following general procedure Y, N-(isopropylideneamino)benzamide (450 mg,2.55 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-100% EtOAc in heptane,N′-(2,2,2-trifluoro-1,1-dimethyl-ethyl)benzohydrazide (277 mg, 1.12mmol, 44% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.50 min, m/z 247.0 [M+H]⁺

(2,2,2-Trifluoro-1,1-dimethyl-ethyl)hydrazine hydrochloride

Following general procedure U,N′-(2,2,2-trifluoro-1,1-dimethyl-ethyl)benzohydrazide (1.12 mmol) gave,without further purification,(2,2,2-trifluoro-1,1-dimethyl-ethyl)hydrazine hydrochloride (1.43 mmol)as an off-white solid. ¹H NMR (400 MHz, MeOD-d₄, δ): 1.42 (s, 6H)

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazole-4-carbonitrile

Following general procedure H,(2,2,2-trifluoro-1,1-dimethyl-ethyl)hydrazine hydrochloride (200 mg,1.12 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(295 mg, 1.12 mmol) gave, crude5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazole-4-carbonitrile(316 mg, 0.85 mmol, 76% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 2.02 min, m/z 375.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazole-4-carbonitrile(216 mg, 0.58 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (833 mg,2.88 mmol) gave, after purification, titled compound (250 mg, 0.52 mmol,91% yield) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.80 min,m/z 476.1 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(250 mg, 0.53 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-100% EtOAc in heptane,followed by SPE SCX cartridge eluting with MeOH, titled compound (0.28mmol, 53% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.64min, m/z 494.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.85 min, m/z 494.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.85 (t, J=6.0 Hz, 1H), 7.52 (dd, J=9.3,3.4 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.31 (m, 1H), 7.19 (dd, J=9.2, 4.3Hz, 1H), 6.51 (br s, 2H), 4.56 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 1.88 (s,6H).

Example 190:5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[4-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carboxamide

N-(Tetrahydropyran-4-ylideneamino)benzamide

Benzhydrazide (633 mg, 4.65 mmol) was added to a solution oftetrahydro-4H-pyran-4-one (0.4 mL, 4.65 mmol) in MeOH (9 mL). Thereaction mixture was stirred at RT for 16 h and concentrated underreduced pressure. Purification afforded N titled compound (920 mg, 4.22mmol, 91% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.05min, m/z 218.9 [M+H]⁺

N′-[4-(Trifluoromethyl)tetrahydropyran-4-yl]benzohydrazide

Following general procedure Y in DCM (9 mL),N-(tetrahydropyran-4-ylideneamino)benzamide (250 mg, 1.15 mmol) gave,after purification, titled compound (329 mg, 1.14 mmol, quantitative) asa white solid.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 289.0 [M+H]⁺

[4-(Trifluoromethyl)tetrahydropyran-4-yl]hydrazine hydrochloride

Following general procedure U,N′-[4-(trifluoromethyl)tetrahydropyran-4-yl]benzohydrazide (329 mg, 1.14mmol) gave crude titled compound (252 mg, 1.14 mmol, assumedquantitative) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆, δ): 3.77-3.68(m, 2H), 3.66-3.55 (m, 2H), 1.87-1.72 (m, 4H)

5-Amino-3-(4-bromophenyl)-1-[4-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carbonitrile

Following general procedure H at 80° C.,[4-(trifluoromethyl)tetrahydropyran-4-yl]hydrazine hydrochloride (252mg, 1.14 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile(250 mg, 0.95 mmol) gave, after purification, titled compound (122 mg,0.29 mmol, 31% yield) as off-white solid. UPLC-MS (ES⁺, Short acidic):1.95 min, m/z 415.0 [M]⁺

N-[[4-[5-amino-4-cyano-1-[4-(trifluoromethyl)tetrahydropyran-4-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[4-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carbonitrile(50 mg, 0.12 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (52 mg,0.18 mmol) gave, after purification, titled compound (62 mg, 0.12 mmol)as an off-white powder.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 518.2 [M+H]⁺

5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[4-(trifluoromethyl)tetrahydropyran-4-yl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[4-(trifluoromethyl)tetrahydropyran-4-yl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(62 mg, 0.12 mmol) gave, after purification by reverse phase columnchromatography eluting with 0-45% MeCN in water with 0.1% formic acidadditive and flash column chromatography on silica gel eluting with 0-7%MeOH in DCM, titled compound (5 mg, 0.01 mmol, 8% yield) as an off-whitesolid. UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 536.2 [M+H]⁺ UPLC-MS(ES⁺, Long acidic): 3.72 min, m/z 536.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.85 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.49-7.41 (m, 4H), 7.38-7.31 (m, 1H), 7.19 (dd, J=9.1, 4.3Hz, 1H), 6.57 (s, 2H), 4.55 (d, J=6.0 Hz, 2H), 3.95-3.86 (m, 5H),3.32-3.24 (m, 2H), 3.02-2.93 (m, 2H), 2.07-1.95 (m, 2H)

Example 191:5-amino-1-(3,3-difluoro-1-methyl-4-piperidyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(3,3-difluoro-1-methyl-4-piperidyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-1-(3,3-difluoro-4-piperidyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide(36 mg, 0.07 mmol) and cesium carbonate (47 mg, 0.14 mmol) weresuspended in DMF (2 mL). The mixture was cooled to 0° C. and a solutionof iodomethane (0.9 M in DMF, 0.1 mL, 0.09 mmol) was added dropwise. Themixture was stirred at RT for 16 h. Work up and purification affordedtitled compound (20 mg, 0.04 mmol, 54% yield) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.18 min, m/z 517.2 [M+H]⁺ UPLC-MS (ES⁺, Longacidic): 2.56 min, m/z 517.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.0 Hz, 1H), 7.52 (dd, J=9.2,3.4 Hz, 1H), 7.47-7.41 (m, 4H), 7.37-7.32 (m, 1H), 7.19 (dd, J=9.1, 4.3Hz, 1H), 6.44 (s, 2H), 4.74-4.63 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.90(s, 3H), 3.17-3.10 (m, 1H), 2.96-2.93 (m, 1H), 2.47-2.38 (m, 2H), 2.29(s, 3H), 2.22-2.16 (m, 1H), 1.94-1.88 (m, 1H).

Example 192:5-amino-1-(1-cyclohexyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[(1-Cyclohexyl-2,2,2-trifluoro-ethylidene)amino]benzamide

Following general procedure S, 1-cyclohexyl-2,2,2-trifluoro-ethanone(5.55 mmol) gave, after purification, titled compound (1.11 mmol).UPLC-MS (ES⁺, Short acidic): 1.92 min, m/z 299.0 [M+H]⁺

N′-(1-Cyclohexyl-2,2,2-trifluoro-ethyl)benzohydrazide

General procedure TN-[(1-cyclohexyl-2,2,2-trifluoro-ethylidene)amino]benzamide (1.11 mmol)gave titled compound (0.64 mmol) as colorless oil. UPLC-MS (ES⁺, Shortacidic): 1.89 min, m/z 301.0 [M+H]⁺

(1-Cyclohexyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride

Following general procedure U,N-(1-cyclohexyl-2,2,2-trifluoro-ethyl)benzohydrazide (0.64 mmol) gave,without further purification, titled compound (0.42 mmol) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆, δ): 5.97 (s, 1H), 1.79-1.66 (m, 5H),1.65-1.57 (m, 1H), 1.37-1.04 (m, 5H)

5-Amino-3-(4-bromophenyl)-1-n-cyclohexyl-2,2,2-trifluoro-ethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.42 mmol) and(1-cyclohexyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride (0.42 mmol)gave titled compound (0.42 mmol) as an orange oil. UPLC-MS (ES⁺, Shortacidic): 2.25 min, m/z 429.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-n-cyclohexyl-2,2,2-trifluoro-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (365 mg,1.26 mmol) and5-amino-3-(4-bromophenyl)-1-(1-cyclohexyl-2,2,2-trifluoro-ethyl)pyrazole-4-carbonitrile (180 mg, 0.42 mmol) gave titled compound (223mg, 0.42 mmol). UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 530.2 [M+H]⁺

5-Amino-1-(1-cyclohexyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(1-cyclohexyl-2,2,2-trifluoro-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(223 mg, 0.42 mmol) gave, after purification, titled compound (72 mg,0.13 mmol, 31% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.83 min, m/z 548.3 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 4.33 min, m/z548.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (t, J=6.1 Hz, 1H), 7.51 (dd, J=9.3,3.3 Hz, 1H), 7.47-7.40 (m, 4H), 7.37-7.30 (m, 1H), 7.18 (dd, J=9.1, 4.4Hz, 1H), 6.69 (br s, 2H), 4.99-4.88 (m, 1H), 4.54 (d, J=6.2 Hz, 2H),3.89 (s, 3H), 2.39-2.25 (m, 1H), 1.93-1.85 (m, 1H), 1.79-1.71 (m, 1H),1.66-1.56 (m, 2H), 1.36-1.11 (m, 5H), 1.04-0.93 (m, 1H).

Example 193:5-Amino-1-[1-(difluoromethyl)-3-hydroxy-propyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Ethyl 3-(tert-butoxycarbonylhydrazono)-4,4-difluoro-butanoate

Following general procedure E at 60° C., tert-butyl carbazate (505 mg,3.82 mmol) and ethyl 4,4-difluoro-3-oxobutanoate (0.5 mL, 3.82 mmol)gave, after purification, titled compound (983 mg, 3.51 mmol, 92% yield)as an off-white solid. UPLC-MS (ES⁻, Short acidic): 1.61 min, m/z 279.0[M−H]⁻

tert-Butyl N-[[1-(difluoromethyl)-3-hydroxy-propyl]amino]carbamate

To a solution of ethyl3-(tert-butoxycarbonylhydrazono)-4,4-difluoro-butanoate (200 mg, 0.71mmol) in THF (1.4 mL) was added borane tetrahydrofuran complex (1 M inTHF, 3.6 mL, 3.60 mmol) at 0° C. The reaction mixture was stirred for 2h at RT. MeOH (3.6 mL) was then added carefully and the mixture was thenconcentrated to afford crude titled compound (171 mg, 0.71 mmol) as abrown oil.

UPLC-MS (ES⁻, Short acidic): 1.24 min, m/z 239.1 [M−H]⁻

5-Amino-3-(4-bromophenyl)-1-[1-(difluoromethyl)-3-hydroxy-propyl]pyrazole-4-carbonitrile

A hydrogen chloride solution (4 M in dioxane, 1.78 mL, 7.14 mmol) wasadded to tert-butylN-[[1-(difluoromethyl)-3-hydroxy-propyl]amino]carbamate (171 mg, 0.71mmol). After 1 h stirring at RT, the mixture was concentrated underreduced pressure. The residue was taken up with EtOH (2.2 mL) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (150 mg, 0.57mmol) was then added, followed by triethylamine (0.2 mL, 1.43 mmol). Thereaction mixture was heated to 80° C. for 30 min, cooled to RT andconcentrated under reduced pressure. Purification afforded titledcompound (143 mg, 0.39 mmol, 68% yield) as an off-white solid. UPLC-MS(ES⁺, Short acidic): 1.67 min, m/z 373.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-1[1-(difluoromethyl)-3-hydroxy-propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[1-(difluoromethyl)-3-hydroxy-propyl]pyrazole-4-carbonitrile(50 mg, 0.13 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (58 mg,0.20 mmol) gave, after purification, titled compound (0.10 mmol) as anoff-white powder. UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 474.2[M+H]⁺

5-Amino-1-[1-(difluoromethyl)-3-hydroxy-propyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[1-(difluoromethyl)-3-hydroxy-propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(46 mg, 0.10 mmol) gave, after purification, titled compound (22 mg,0.05 mmol, 47% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.38 min, m/z 492.2 [M+F1]⁺ UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z492.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=5.9 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.49-7.39 (m, 4H), 7.38-7.30 (m, 1H), 7.19 (dd, J=9.1, 4.3Hz, 1H), 6.51 (s, 2H), 6.25 (dt, J=55.5, 4.9 Hz, 1H), 4.84-4.66 (m, 2H),4.55 (d, J=6.1 Hz, 2H), 3.90 (s, 3H), 3.48-3.36 (m, 1H), 3.28-3.15 (m,1H), 2.28-2.13 (m, 1H), 2.06-1.87 (m, 1H)

Example 194:5-amino-1-[2,2-dimethyl-1-(trifluoromethyl)propyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-(2,2-Dimethylpropylideneamino)benzamide

Following general procedure S, benzhydrazide (300 mg, 2.20 mmol) andpivalaldehyde (0.40 mL, 3.31 mmol) afforded, after purification, titledcompound (407 mg, 1.99 mmol, 90% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 205.0 [M+H]⁺

N′-[2,2-Dimethyl-1-(trifluoromethyl)propyl]benzohydrazide

Following general procedure Y, N-(2,2-dimethylpropylideneamino)benzamide(407 mg, 1.99 mmol) afforded, after purification, titled compound (492mg, 1.79 mmol, 90% yield) as a white solid. UPLC-MS (ES⁺, Short acidic):1.74 min, m/z 275.0 [M+H]⁺

[2,2-Dimethyl-1-(trifluoromethyl)propyl]hydrazine hydrochloride

Following general procedure U,N′-[2,2-dimethyl-1-(trifluoromethyl)propyl]benzohydrazide (492 mg, 1.79mmol) afforded crude titled compound (371 mg, 1.79 mmol, assumedquantitative yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, δ):6.09-5.98 (m, 1H), 1.04 (s, 9H).

5-Amino-3-(4-bromophenyl)-1-[2,2-dimethyl-1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (100 mg, 0.38mmol) and [2,2-dimethyl-1-(trifluoromethyl)propyl]hydrazinehydrochloride (118 mg, 0.57 mmol) afforded crude titled compound (152mg, 0.38 mmol, assumed quantitative yield) as a yellow solid. UPLC-MS(ES⁺, Short acidic): 2.16 min, m/z 403.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-[2,2-dimethyl-1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-[2,2-dimethyl-1-(trifluoromethyl)propyl]pyrazole-4-carbonitrile(168 mg, 0.42 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (243 mg,0.84 mmol) afforded, after purification, titled compound (208 mg, 0.41mmol, 98% yield) as a yellow gum. UPLC-MS (ES⁺, Short acidic): 1.90 min,m/z 504.1 [M+H]⁺

5-Amino-1-[2,2-dimethyl-1-(trifluoromethyl)propyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-[2,2-dimethyl-1-(trifluoromethyl)propyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(208 mg, 0.41 mmol) afforded, after purification, (54 mg, 0.09 mmol, 22%yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 522.2 [M+H]⁺ UPLC-MS (ES⁺,Long acidic): 4.19 min, m/z 522.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.5-7.4 (m, 4H), 7.38-7.30 (m, 1H), 7.22-7.16 (m, 1H), 6.76(s, 2H), 5.03-4.94 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 3.89 (s, 3H), 1.11(s, 9H).

Example 195:5-amino-1-ethyl-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-ethyl-pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (263 mg, 1.0 mmol)and ethylhydrazine oxalate (150 mg, 1.0 mmol) gave titled compound (210mg, 0.7 mmol, 72% yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic):1.69 min, m/z 292.9 [M+2]⁺

N-[[4-(5-Amino-4-cyano-1-ethyl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-ethyl-pyrazole-4-carbonitrile (0.21 g, 0.72mmol), and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (1.04 g,3.59 mmol) gave, after purification, titled compound (0.28 g, 0.71 mmol,99% yield) as an off-white solid. UPLC-MS (ES⁺, Short acidic): 1.53 min,m/z 394.2 [M+H]⁺

5-Amino-1-ethyl-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-(5-amino-4-cyano-1-ethyl-pyrazol-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(207 mg, 0.53 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 0-100% EtOAc in heptane,followed by further purification by SPE SCX cartridge eluting with MeOH,titled compound (96 mg, 0.23 mmol, 44% yield) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.34 min, m/z 412.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.04 min, m/z 412.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.3 Hz, 1H), 7.52 (dd, J=9.0,3.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.38-7.31(m, 1H), 7.19 (dd, J=9.2, 4.2 Hz, 1H), 6.32 (br s, 2H), 4.55 (d, J=6.1Hz, 2H), 3.95 (q, J=7.2 Hz, 2H), 3.90 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

Example 196:5-Amino-1-(1-cyclopentyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

N-[Cyclopentylmethyleneamino]benzamide

To a solution of benzhydrazide (300 mg, 2.20 mmol) in toluene (4.40 mL)was added cyclopentane carbaldehyde (0.25 mL, 3.31 mmol). The reactionmixture was heated to 110° C. for 16 h, cooled to RT and poured intowater (20 mL). Work up afforded crude titled compound (420 mg, 1.94mmol, 88% yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.42min, m/z 217.0 [M+H]⁺

N′-(1-Cyclopentyl-2,2,2-trifluoro-ethyl)benzohydrazide

Following general procedure Y, N-[cyclopentylmethyleneamino]benzamide(420 mg, 1.94 mmol) and trimethyl(trifluoromethyl)silane (0.57 mL, 3.88mmol) afforded N′-(1-cyclopentyl-2, 2,2-trifluoro-ethyl)benzohydrazide(556 mg, 1.94 mmol). UPLC-MS (ES⁺, Short acidic): 1.81 min, m/z 287.0[M+H]⁺

(1-Cyclopentyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride

Following general procedure U,N′-(1-Cyclopentyl-2,2,2-trifluoro-ethyl)benzohydrazide (1.94 mmol) gave(1-cyclopentyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride (1.83 mmol)as an off-white solid. ¹H NMR (400 MHz, CDCl₃, δ): 3.81-3.69 (m, 1H),2.07-2.01 (m, 1H), 1.85-1.70 (m, 2H), 1.64-1.57 (m, 2H), 1.52-1.40 (m,4H)

5-Amino-3-(4-bromophenyl)-1-n-cyclopentyl-2,2,2-trifluoro-ethyl)pyrazole-4-carbonitrile

Following general procedure H,2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (0.70 mmol) and(1-cyclopentyl-2,2,2-trifluoro-ethyl)hydrazine hydrochloride (0.84 mmol)afforded, after purification, titled compound (0.12 mmol) as a yellowoil. UPLC (ES⁺, Short acidic): 2.91 min, m/z 415.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-n-cyclopentyl-2,2,2-trifluoro-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (108 mg,0.37 mmol) and5-amino-3-(4-bromophenyl)-1-(1-cyclopentyl-2,2,2-trifluoro-ethyl)pyrazole-4-carbonitrile(91 mg, 0.22 mmol) afforded, after purification, titled compound (112mg, 0.22 mmol, 98% yield) as an off-white solid. LC-MS (ES⁺, ShortAcidic): 5.58 min, m/z 516.1 [M+H]⁺

5-Amino-1-(1-cyclopentyl-2,2,2-trifluoro-ethyl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(1-cyclopentyl-2,2,2-trifluoro-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(112 mg, 0.22 mmol) afforded, after purification, titled compound (18mg, 0.03 mmol, 15%) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.71min, m/z 534.2 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 4.17 min, m/z 534.2[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.84 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.48-7.39 (m, 4H), 7.38-7.30 (m, 1H), 7.19 (dd, J=9.1, 4.3Hz, 1H), 6.71 (s, 2H), 5.05-4.93 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 3.90(s, 3H), 2.79-2.69 (m, 1H), 1.94-1.81 (m, 1H), 1.80-1.32 (m, 6H),1.22-1.08 (m, 1H)

Example 197:5-amino-1-(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

4,4-Difluoro-1-isopropyl-pyrrolidin-3-ol

A mixture of 4,4-difluoropyrrolidin-3-ol (300 mg, 2.44 mmol), acetone(0.27 mL, 3.66 mmol) and glacial acetic acid (0.21 mL, 3.66 mmol) in THF(9.8 mL) was stirred for 30 min at RT. Sodium diacetoxy(acetyl)boranuide(716 mg, 3.66 mmol) was then added and the reaction was stirred for 3 hat RT. The reaction mixture was diluted with a saturated solution ofsodium bicarbonate and following work up and purification affordedtitled compound (178 mg, 1.08 mmol, 44% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃, δ): 4.25-4.18 (m, 1H), 3.10-3.00 (m, 3H),2.70-2.65 (m, 1H), 2.59-2.49 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 1.04 (d,J=6.4 Hz, 3H)

5-Amino-3-(4-bromophenyl)-1-(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl)pyrazole-4-carbonitrile

A solution of 4,4-difluoro-1-isopropyl-pyrrolidin-3-ol (178 mg, 1.08mmol) in anhydrous DCM (20 mL) was cooled to −20° C. and purged withnitrogen. Trifluoromethanesulfonic anhydride (1 M in DCM, 2.69 mL, 2.69mmol) was added and the reaction mixture was stirred for 40 min, beforebeing quenched with water. Work up afforded crude(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl) trifluoromethanesulfonate(31.08 mmol) as a red oil. Following general procedure N, the crudecompound and 5-amino-3-(4-bromophenyl)-1H-pyrazole-4-carbonitrile (1.06mmol) afforded, after purification, titled compound (0.31 mmol) as apale yellow oil. UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 412.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (155 mg,0.54 mmol) and5-amino-3-(4-bromophenyl)-1-(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl)pyrazole-4-carbonitrile(129 mg, 0.32 mmol) afforded, after purification, titled compound (88mg, 0.17 mmol, 54% yield) as a yellow oil.

UPLC-MS (ES⁻, Short Acidic): 1.48 min, m/z 511.2 [M−H]⁻

5-Amino-1-(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(4,4-difluoro-1-isopropyl-pyrrolidin-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(88 mg, 0.17 mmol) afforded, after purification, titled compound (35 mg,0.07 mmol, 38%) as an off-white solid. UPLC-MS (ES⁺, Short Acidic): 1.30min, m/z 531.3 [M+H]⁺ UPLC-MS (ES⁺, Long Acidic): 2.83 min, m/z 531.4[M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.86 (t, J=6.1 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.46-7.41 (m, 4H), 7.37-7.33 (m, 1H), 7.19 (dd, J=9.1, 4.3Hz, 1H), 6.62 (s, 2H), 5.21-5.14 (m, 1H), 4.55 (d, J=6.1, 2H), 3.90 (s,3H), 3.26-3.17 (m, 2H), 2.98-2.89 (m, 1H), 2.62-2.57 (m, 1H), 2.53-2.40(m, 1H), 1.06-1.03 (m, 6H)

Example 198:-amino-1-(1-ethyl-4,4-difluoro-pyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

1-Ethyl-4,4-difluoro-pyrrolidin-3-ol

A mixture of 4,4-difluoropyrrolidin-3-ol dihydrochloride (1.02 mmol),acetaldehyde (1.53 mmol), glacial acetic acid (1.53 mmol) in THF (6.5mL) was stirred for 1 h at RT. Sodium diacetoxy(acetyl)boranuide (1.53mmol) was then added and the reaction was stirred for 3 h. Work up andpurification afforded titled compound (94 mg, 0.62 mmol, 61% yield) as ayellow oil. ¹H NMR (400 MHz, CDCl₃, δ): 4.25-4.18 (m, 1H), 3.07-2.91 (m,3H), 2.64-2.60 (m, 1H), 2.53 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H)

(1-Ethyl-4,4-difluoro-pyrrolidin-3-yl) trifluoromethanesulfonate

A solution of 1-ethyl-4,4-difluoro-pyrrolidin-3-ol (94 mg, 0.62 mmol) inanhydrous DCM (20 mL), was cooled to −20° C. and purged with nitrogen.Trifluoromethanesulfonic anhydride (1 M in DCM, 1.55 mL, 1.55 mmol) wasthen added. The reaction mixture was stirred for 40 min at the sametemperature. Work up afforded crude titled compound (94 mg, 0.33 mmol,53% yield) as a red oil.

¹H NMR (400 MHz, CDCl₃, δ): 5.08-5.03 (m, 1H), 3.25-3.21 (m, 1H),3.10-3.04 (m, 1H), 2.98-2.87 (m, 1H), 2.83-2.78 (m, 1H), 2.52 (q, J=7.2Hz, 2H), 1.04 (t, J=7.2 Hz, 3H)

5-Amino-3-(4-bromophenyl)-1-n-ethyl-4,4-difluoro-pyrrolidin-3-yl)pyrazole-4-carbonitrile

Following general procedure N, (1-ethyl-4,4-difluoro-pyrrolidin-3-yl)trifluoromethanesulfonate (93 mg, 0.33 mmol) and5-amino-3-(4-bromophenyl)-1H-pyrazole-4-carbonitrile (72 mg, 0.27 mmol)afforded, after purification, titled compound (60 mg, 0.15 mmol, 55%yield) as a yellow solid. UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z398.0 [M+2]⁺

N-[[4-[5-Amino-4-cyano-1-(1-ethyl-4,4-difluoro-pyrrolidin-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (74 mg,0.26 mmol) and5-amino-3-(4-bromophenyl)-1-(1-ethyl-4,4-difluoro-pyrrolidin-3-yl)pyrazole-4-carbonitrile(60 mg, 0.15 mmol) afforded, after purification, titled compound (30 mg,0.06 mmol, 39% yield) as a colourless oil. UPLC-MS (ES⁻, Short acidic):1.42 min, 497.2 m/z [M−H]⁻

5-Amino-1-(1-ethyl-4,4-difluoro-pyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(1-ethyl-4,4-difluoro-pyrrolidin-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(29 mg, 0.06 mmol) afforded, after purification, titled compound (5 mg,0.01 mmol, 16% yield) as an off-white solid. UPLC-MS (ES⁺, ShortAcidic): 1.26 min, m/z 517.2 [M+H]⁺ UPLC-MS (ES⁺, Long Acidic): 2.74min, m/z 517.2 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.86 (t, J=6.0 Hz, 1H), 7.51 (dd, J=9.2,3.3 Hz, 1H), 7.46-7.41 (m, 4H), 7.37-7.33 (m, 1H), 7.19 (dd, 9.1, 4.2Hz, 1H), 6.60 (s, 2H), 5.22-5.15 (m, 1H), 4.55 (d, J=6.1 Hz, 2H), 3.89(s, 3H), 3.30-3.15 (m, 2H), 2.91-2.77 (m, 1H), 2.69-2.36 (m, 3H), 1.05(t, J=7.2 Hz, 3H).

Example 199:5-amino-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

4,4-Difluoro-1-methyl-pyrrolidin-3-ol

Paraformaldehyde (64 mg, 1.33 mmol) and sodium hydroxide (53 mg, 1.33mmol) were suspended in THF (12 mL) and stirred for 20 min.4,4-Difluoropyrrolidin-3-ol dihydrochloride (520 mg, 2.65 mmol) andformic acid (0.25 mL, 6.63 mmol) were then added and the reaction washeated to reflux for 2 h. The mixture was cooled to 0° C., diluted withNaOH (10 N, 1 mL) and extracted with diethyl ether (×2). The combinedorganic layers were dried over a hydrophobic frit and concentrated underreduced pressure to give 4,4-difluoro-1-methyl-pyrrolidin-3-ol (269 mg,1.96 mmol, 74% yield) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃, δ): 4.27-4.17 (m, 1H), 3.05-3.01 (m, 1H),3.00-2.91 (m, 2H), 2.63-2.59 (m, 1H), 2.38 (s, 3H).

(4,4-Difluoro-1-methyl-pyrrolidin-3-yl) trifluoromethanesulfonate

4,4-Difluoro-1-methyl-pyrrolidin-3-ol (268 mg, 1.95 mmol) was dissolvedin anhydrous DCM (20 mL) in a 3-neck flask. The solution was cooled to−20° C. and flushed with nitrogen (×3). Trifluoromethanesulfonicanhydride (1 M in DCM, 4.87 mL, 4.87 mmol) was slowly added. The mixturewas stirred at −20-−10° C. for 40 min. Work up afforded titled compound(429 mg, 1.60 mmol, 81% yield) as a red oil which was used withoutfurther purification.

¹H NMR (400 MHz, CDCl₃, δ): 5.07-5.02 (m, 1H), 3.19-3.15 (m, 1H),3.03-2.88 (m, 2H), 2.80-2.77 (m, 1H), 2.34 (s, 3H)

5-Amino-3-(4-bromophenyl)-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)pyrazole-4-carbonitrile

Following general procedure N, (4,4-difluoro-1-methyl-pyrrolidin-3-yl)trifluoromethanesulfonate (235 mg, 0.87 mmol) and5-amino-3-(4-bromophenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.05 mmol)afforded, after purification, titled compound (177 mg, 0.46 mmol, 53%yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 383.8 [M+H]⁺

N-[[4-[5-Amino-4-cyano-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (228 mg,0.79 mmol) and5-amino-3-(4-bromophenyl)-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)pyrazole-4-carbonitrile(177 mg, 0.46 mmol) afforded, after purification, titled compound (0.06mmol) as a yellow oil. UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 485.2[M+H]⁺

5-Amino-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(4,4-difluoro-1-methyl-pyrrolidin-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(31 mg, 0.06 mmol) afforded, after purification, titled compound (6 mg,0.01 mmol, 19% yield) as an off white solid. UPLC-MS (ES⁺, Shortacidic): 1.23 min, m/z 503.3 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 2.70min, m/z 503.2 [M+H]⁺

¹H NMR (500 MHz, DMSO, d₆, δ): 8.84 (t, J=6.1 Hz, 1H), 7.52 (dd, J=9.2,3.3 Hz, 1H), 7.46-7.41 (m, 4H), 7.37-7.32 (m, 1H), 7.19 (dd, J=9.1, 4.3Hz, 1H), 6.58 (br s, 2H), 5.21-5.17 (m, 1H), 4.55 (d, J=6.1 Hz, 2H),3.90 (s, 3H), 3.34-3.15 (m, 2H), 2.91-2.73 (m, 1H), 2.61-2.42 (m, 1H),2.36 (s, 3H)

Example 200:5-amino-1-(4,4-difluorotetrahydrofuran-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

5-Amino-3-(4-bromophenyl)-1-(4,4-difluorotetrahydrofuran-3-yl)pyrazole-4-carbonitrile

To a solution of 4,4-difluorotetrahydrofuran-3-ol (215 mg, 1.73 mmol)and pyridine (0.70 mL, 8.66 mmol) in dry DCM (1 mL), at −15° C. undernitrogen, was added dropwise a solution trifluoromethanesulfonicanhydride in DCM (1 M, 4.30 mL, 4.30 mmol). The reaction was stirredbetween −15 and −5° C. for 60 min, quenched with water. Work up gave5-amino-3-(4-bromophenyl)-1H-pyrazole-4-carbonitrile. The crude material(90 mg, 0.34 mmol) and cesium carbonate (223 mg, 0.68 mmol) in DMF (3mL) were heated to 90° C. for 16 h. Work up and purification affordedtitled compound (63 mg, 0.14 mmol, 40% yield) as a white solid. UPLC-MS(ES⁺, Short acidic): 1.83 min, m/z 369.0 [M]⁺

N-[[4-[5-Amino-4-cyano-1-(4,4-difluorotetrahydrofuran-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,5-amino-3-(4-bromophenyl)-1-(4,4-difluorotetrahydrofuran-3-yl)pyrazole-4-carbonitrile(63 mg, 0.17 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (94 mg,0.33 mmol) gave, after purification, titled compound (66 mg, 0.12 mmol,68% yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z471.1 [M+H]⁺

5-Amino-1-(4,4-difluorotetrahydrofuran-3-yl)-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Following general procedure M,N-[[4-[5-amino-4-cyano-1-(4,4-difluorotetrahydrofuran-3-yl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(62 mg, 0.13 mmol) gave, after purification, titled compound (25 mg,0.05 mmol, 39% yield) as a light yellow solid. UPLC-MS (ES⁺, Shortacidic): 1.50 min, m/z 490.2 [M+E1]⁺ UPLC-MS (ES⁺, Long acidic): 3.39min, m/z 490.2 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.84 (t, J=6.1 Hz, 1H), 7.52 (dd, J=9.2,3.4 Hz, 1H), 7.48-7.42 (m, 4H), 7.37-7.32 (m, 1H), 7.19 (dd, J=9.2, 4.3Hz, 1H), 6.60 (br s, 2H), 5.37-5.30 (m, 1H), 4.55 (d, J=6.1 Hz, 2H),4.47-4.41 (m, 2H), 4.16-4.10 (m, 1H), 4.05-3.96 (m, 1H), 3.90 (s, 3H).

Example 201: BTK^(WT) Binding Affinity

BTK^(WT) binding affinity of each compound tested was determined using atime-resolved fluorescence resonance energy transfer (TR-FRET)methodology. 2.5 nM Recombinant BTK^(WT) kinase, varying concentrationsof inhibitor, 2 nM LanthaScreen™ Eu anti-His Antibody and 15 nM KinaseTracer 236 was incubated in 1× LanthaScreen™ Kinase Buffer A for 5 h.Recombinant BTK kinase and all LanthaScreen™ components were purchasedfrom Invitrogen. Measurements were performed in a reaction volume of 30μL using half-area 96-well assay plates. The TR-FRET signal was read ona plate reader with an excitation wavelength of 340 nm and detectionwavelengths of 615 and 665 nm. Binding affinity was determined for eachcompound by measuring TR-FRET signal at various concentrations ofcompound and plotting the relative fluorescence units against theinhibitor concentration to estimate the IC₅₀ from log[Inhibitor] vsresponse using the Variable Slope model in Graphpad prism from Graphpadsoftware (San Diego, Calif.).

Results of the BTK^(WT) Binding Affinity are shown below in Table 4

Table 4 shows the BTK^(WT) Binding affinity, as determined by the assaydescribed above, for compounds of formula (I), categorised based on theBTK IC₅₀ value of the compound as “A”, “B”, “C”, “D” and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

Example 202: BTK^(C481S) Binding Affinity

BTK^(C481S) binding affinity of each compound tested was determinedusing a time-resolved fluorescence resonance energy transfer (TR-FRET)methodology. 5 nM Recombinant BTK^(WT) kinase, varying concentrations ofinhibitor, 2 nM LanthaScreen™ Eu anti-Elis Antibody and nM Kinase Tracer236 was incubated in IX LanthaScreen™ Kinase Buffer A for 5 h.Recombinant BTK^(C481S) kinase was purchased from SignalChem and allLanthaScreen™ components were purchased from Invitrogen. Measurementswere performed in a reaction volume of 30 μL using half-area 96-wellassay plates. The TR-FRET signal was read on a plate reader with anexcitation wavelength of 340 nm and detection wavelengths of 615 and 665nm. Binding affinity was determined for each compound by measuringTR-FRET signal at various concentrations of compound and plotting therelative fluorescence units against the inhibitor concentration toestimate the IC₅₀ from log[Inhibitor] vs response using the VariableSlope model in Graphpad prism from Graphpad software (San Diego,Calif.).

Table 4 shows the BTK^(C481S) Binding affinity, as determined by theassay described above, for compounds of formula (I), categorised basedon the BTK IC₅₀ value of the compound as “A”, “B”, “C”, “D” and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

Example 203: EGFR Binding Affinity

EGFR binding affinity was determined using a time-resolved fluorescenceresonance energy transfer (TR-FRET) methodology. 2.5 nM RecombinantEGFR, varying concentrations of inhibitor, 2 nM LanthaScreen™ Euanti-GST Antibody and 3 nM Kinase Tracer 199 was incubated in IXLanthaScreen™ Kinase Buffer A for 5 h. Recombinant EGFR and allLanthaScreen™ components were purchased from Invitrogen. Measurementswere performed in a reaction volume of 30 μL using half-area 96-wellassay plates. The TR-FRET signal was read on a plate reader with anexcitation wavelength of 340 nm and detection wavelengths of 615 and 665nm. Binding affinity was determined for each compound by measuringTR-FRET signal at various concentrations of compound and plotting therelative fluorescence units against the inhibitor concentration toestimate the IC₅₀ from log[Inhibitor] vs response using the VariableSlope model in Graphpad prism from Graphpad software (San Diego,Calif.).

Table 4 shows the EGFR Binding Affinity, as determined by the assaydescribed above, for compounds of formula (I), categorised based on theEGFR IC₅₀ value of the compound as “A”, “B”, “C”, “D” and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

Example 204: OCI-Ly10 Anti-Proliferative Activity

Compounds were assayed for effects on the growth of OCI-Ly10 human DLBCLcells that are dependent on NFκB signalling. OCI-Ly10 cells were grownin suspension in T225 flasks, centrifuged and re-suspended in 2.5% FBScontaining media. Cells were then plated at 7.5×10³ cells per well in96-well plates in varying concentrations of compound and incubated for72 h at 37° C. An additional plate of cells to be used as the Day 0 readwas seeded without compound addition, Resazurin was added to each well,incubated for 5 h and the fluorescence measured at 590 nm. After 72 h ofcompound treatment, Resazurin was added to each well of the compoundtreated plates, incubated for 5 h and the fluorescence measured at 590nm. The IC₅₀ was then calculated by subtracting the average Day 0 valuefrom each well value from the treated plates, each treatment was thencalculated as a percentage of the DMSO control and the percentagesplotted against the inhibitor concentration to estimate the IC₅₀ fromlog[Inhibitor] vs response using the Variable Slope model in Graphpadprism from Graphpad software (San Diego, Calif.).

Table 4 shows the OCI-Ly10 anti-proliferative activity, as determined bythe assay described above, for compounds of formula (I), categorisedbased on the OCI-Ly10 IC₅₀ value of the compound as “A”, “B”, “C”, “D”and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

TABLE 4 LanthaScreen LanthaScreen LanthaScreen Proliferation BindingBinding Binding Assay OCI-Ly10 - Example BTK WT BTK C481S EGFR 20% FBS200 A A D B 199 A A D B 198 A A D B 197 A A D B 196 B B D C 195 A A D B194 B B D C 193 B A D C 192 B B D C 191 A A D B 190 C B D D 189 A A D B188 A A D ND 187 C C D C 186 A A D B 185 D D D ND 184 B A E A 183 A A DC 182 B A D C 181 A A D B 180 A A D B 179 A A D B 178 B A D B 177 A A DB 176 A A D B 175 B B D C 174 A A D B 173 A A D B 172 A A D C 171 B A DC 170 B A D C 169 A A D B 168 B A D B 167 A A D B 166 B A D B 165 B A DB 164 A A D B  163b A A D B  163a A A D A 162 A A D B 161 B A E C 160 BA D C 159 A A E B 158 B B E C 157 A A E B 156 A A E B 155 A A D B 154 AA E B 153 B A E C 152 B B E C 151 A A D C 150 A A D B 149 A A E B 148 BA E C 147 A A D B 146 A A E C 145 B B E C 144 A A C C 143 B A E C 142 AA D C 141 B A E C 140 A A E C 139 B A E C 138 B B E C 137 A A D B 136 AA D B 135 B A E D 134 B B E D 133 C B E ND 132 C B E ND 131 A A C B 130A A D B 129 A A D C 128 A A D B 127 A A D B 126 B A D C 125 B A E C 124B B D C 123 A A D C 122 A A D B 121 A A C B 120 A A D B 119 A A D B 118C B D D 117 A A D B 116 B A D C 115 A A D B 114 A A D B 113 A A D B 112C C E E 111 A A C C 110 B B D D 109 A A D C 108 B B E D 107 A A E B 106A A E C 105 B A D C 104 B A D C 103 A A D B 102 A A E C 101 B A E C 100B A E C  99 B A E C  98 A A D C  97 B A D D  96 A A D B  95 B A D C  94B A D D  93 A A C B  92 A A E B  91 B A D C  90 B A D C  89 B B D D  88A A C A  87 A A C C  86 A A C C  85 A A C B  84 B A D D  83b A A D B 83a A A D C  82 B B D D  81 A A C B  80 A A C B  79 C C D D  78 B B E D 77 A A C B  76 A A C B  75 A A C C  74 A A C D  73 A A C B  72 B A D C 71 A A C B  70 A A C B  69 E ND ND ND  68 A A C B  67 C ND ND ND  66 BA D D  65 A A C B  64 A A C B  63 A A C B  62 A A C B  61 A A C B  60 AA C B  59 A A D B  58 A A D B  57b A A C C  57a A A C B  56 C C ND D  55A A C B  54 B A D C  53 A A C B  52 A A C B  51 A A C B  50 A A C B  49A A C B  48 A A C C  47 B A D C  46 A A C B  45 A A D B  44 A A C B  43A A C B  42 E ND E ND  41 A A C B  40 A A C B  39 A A C B  38 E D E E 37 A A C B  36 A A D B  35 A A D B  34b A A D B  34a A A C B  33 A A CB  32 A A C B  31 B B E D  30 B B E C  29 A A D C  28 A A C B  27 A A CB  26 A A B A  25 B A D E  24 B B D C  23 A A C B  22 A A D B  21 A A CC  20 A A C B  19 A A C B  18 A A C A  18 A A C B  17 A A C B  16 B A DC  15 A A D B  14 B B D C  13 A A D C  12 C C E D  11 B B D D  10 B B DC  9 B B D C  8 C B E C  7 C B E C  6 B A E C  5 A A C B  4 A A C A  3 AA C B  2 A A ND C  1 A A C A

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

1. A compound according to formula (I) or pharmaceutically acceptablesalts thereof:

wherein R¹ may be selected from:

R² represents a group selected from: halo, C₁₋₈ alkyl, C₁₋₈ haloalkyl or—NR^(C)R^(D), wherein R^(C) and R^(D) are, at each occurrence,independently selected from: H or C₁₋₄ alkyl, R³ represents —C(O)NH₂,—C(O)NHMe, —CH₂OH, CH(OH)CH₃, —CF₃, or —CHF₂, R^(4a) and R^(4b) are H,R⁵ is H, R⁶ is methoxyphenyl or methoxyfluorophenyl, A is unsubstitutedphenyl or phenyl substituted by one or two R⁷, wherein R⁷ is selectedfrom: fluoro, methyl, methoxy, and —CH₂OH, and m is
 1. 2. The compoundaccording to claim 1 wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 3 wherein R¹ is:

or a pharmaceutically acceptable salt thereof.
 5. The compound accordingto claim 3 wherein R¹ is:


6. A compound of the formula:

wherein * indicates a chiral center, or a pharmaceutically acceptablesalt thereof.
 7. The compound according to claim 6 wherein the chiralcenter * is in the (S)-configuration.
 8. A pharmaceutical composition,wherein the pharmaceutical composition comprises a compound of claim 1or a pharmaceutically acceptable salt thereof and pharmaceuticallyacceptable excipients.
 9. A pharmaceutical composition, wherein thepharmaceutical composition comprises a compound of claim 5 or apharmaceutically acceptable salt thereof, and pharmaceuticallyacceptable excipients.
 10. A pharmaceutical composition, wherein thepharmaceutical composition comprises a compound of claim 6 or apharmaceutically acceptable salt thereof and pharmaceutically acceptableexcipients.
 11. A pharmaceutical composition, wherein the pharmaceuticalcomposition comprises a compound of claim 7 or a pharmaceuticallyacceptable salt thereof and pharmaceutically acceptable excipients. 12.A method of treating a condition which is modulated by BTK in a patientin need thereof comprising administering to the patient a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof. 13.The method according to claim 12 wherein the condition modulated by BTKis cancer, lymphoma, leukemia, autoimmune diseases, inflammatorydisorders, heteroimmune conditions, or fibrosis.
 14. The methodaccording to claim according to claim 13 wherein the condition modulatedby BTK is selected from B-cell malignancy, B-cell lymphoma, diffuselarge B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkinlymphoma, ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairycell leukemia, B-cell non-Hodgkin lymphoma, Waldenstrom'smacroglobulinemia, multiple myeloma, bone cancer, bone metastasis,arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease, Sjögren's syndrome, andlupus.
 15. The method according to claim 13 wherein the conditionmodulated by BTK is selected from arthritis, multiple sclerosis,osteoporosis, irritable bowel syndrome, inflammatory bowel disease,Crohn's disease, and lupus.
 16. A method of treating a condition whichis modulated by BTK in a patient in need thereof comprisingadministering to the patient a compound according to claim 5 or apharmaceutically acceptable salt thereof.
 17. The method according toclaim 16 wherein the condition modulated by BTK is cancer, lymphoma,leukemia, autoimmune diseases, inflammatory disorders, heteroimmuneconditions, or fibrosis.
 18. The method according to claim according toclaim 17 wherein the condition modulated by BTK is selected from B-cellmalignancy, B-cell lymphoma, diffuse large B cell lymphoma, chroniclymphocytic leukemia, non-Hodgkin lymphoma, ABC-DLBCL, mantle celllymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkinlymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bonecancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis,irritable bowel syndrome, inflammatory bowel disease, Crohn's disease,Sjögren's syndrome, and lupus.
 19. The method according to claim 17wherein the condition modulated by BTK is selected from arthritis,multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatorybowel disease, Crohn's disease, and lupus.
 20. A method of treating acondition which is modulated by BTK in a patient in need thereofcomprising administering to the patient a compound according to claim 6or a pharmaceutically acceptable salt thereof.
 21. The method accordingto claim 20 wherein the condition modulated by BTK is cancer, lymphoma,leukemia, autoimmune diseases, inflammatory disorders, heteroimmuneconditions, or fibrosis.
 22. The method according to claim according toclaim 21 wherein the condition modulated by BTK is selected from B-cellmalignancy, B-cell lymphoma, diffuse large B cell lymphoma, chroniclymphocytic leukemia, non-Hodgkin lymphoma, ABC-DLBCL, mantle celllymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkinlymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bonecancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis,irritable bowel syndrome, inflammatory bowel disease, Crohn's disease,Sjögren's syndrome, and lupus.
 23. The method according to claim 21wherein the condition modulated by BTK is selected from arthritis,multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatorybowel disease, Crohn's disease, and lupus.
 24. A method of treating acondition which is modulated by BTK in a patient in need thereofcomprising administering to the patient a compound according to claim 7or a pharmaceutically acceptable salt thereof.
 25. The method accordingto claim 24 wherein the condition modulated by BTK is cancer, lymphoma,leukemia, autoimmune diseases, inflammatory disorders, heteroimmuneconditions, or fibrosis.
 26. The method according to claim according toclaim 25 wherein the condition modulated by BTK is selected from B-cellmalignancy, B-cell lymphoma, diffuse large B cell lymphoma, chroniclymphocytic leukemia, non-Hodgkin lymphoma, ABC-DLBCL, mantle celllymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkinlymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bonecancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis,irritable bowel syndrome, inflammatory bowel disease, Crohn's disease,Sjögren's syndrome, and lupus.
 27. The method according to claim 25wherein the condition modulated by BTK is selected from arthritis,multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatorybowel disease, Crohn's disease, and lupus.